Renal Tubular Handling of Drugs
EDWARD J. CAFRUNY,
M.D., Ph.D.
New York, New York
From the Department of Pharmacology, Cornell University Medical College, New York, New York. Part of this study was supported by Grant AM13152 from the National Institutes of Health. Requests for reprints should be addressed to the Department of Pharmacology, Cornell University Medical College, 1300 York Avenue, New York, New York 10021.
490
April 1977
The renal excretion of drugs is a vectorial quantity, the resultant of physiologic mechanisms that have directtonal orientation and magnitude. Magnitude is limited by a variety of extrarenal factors including plasma protein binding and the volume of the total body water. The contributions of the glomeruli and tubules to excretion varies with age. This fact has clinical relevance, especially in newborn children and older patients. Although protein binding reduces the amount of a drug that can be filtered, it usually does not alter the rate of proximal tubular secretion of charged organic molecules. Reabsorption of the filtered fluid from tubular lumens creates concentration gradients favoring the reabsorption of drugs, but the movement of drug molecules out of luminal fluid is hindered by the formation of polar drug metabolites in the liver. Although there are only a few examples in the literature, it is probable that many drugs are reabsorbed by a carrier-mediated process located In the proximal tubules. A major difference exists between the renal handling of chlormerodrin, a neutral mercurial, and of mersalyl, an acidic mercurial. Chlormerodrin is reabsorbed (as a complex with cystelne) by a carrier-mediated process; mersalyl is secreted by one of the organic anion transport systems. Most of the useful information we possess on the renal tubular handling of drugs has been acquired in the last two decades, a period during which major advances in the development of analytical methods have been made. This information is still incomplete for each drug studied, and we continue to add new facts and figures. Much of the new data we are gathering have direct clinical application, and all careful studies in this field contribute to our understanding of renal function in health and disease. Any evaluation of the renal tubular handling of drugs hinges on an understanding of the forces involved in the operation of renal tubular transport mechanisms, for these forces apply to ali substances delivered to the kidney. The rate of excretion of any drug may be thought of as a vectorial quantity, the sum or resultant of a number of forces, each of which has magnitude and direction. Magnitude is dependent both on extrarenal factors (e.g., protein binding, drug metabolism, the force of cardiac contraction) and on renal forces (e.g., electrochemical gradients, active transport systems, urinary pH). Direction, on the other hand, is determined entirely by the structural components of the kidney which govern the orientation and capacity of its transporting functions. The sum or resultant vector applicable to the excretion of a number of drugs can be broken down into measurable components. Analysis
The American Journal of Medlclne
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RENAL TUBULAR HANDLING OF DRUGS--CAFRUNY
TABLE
I
Glomerular
Basic Feature Driving force
Primary orientation Solute characteristics Directional orientation
and Proximal Glomerular
Tubular
Excretion
Proximal Tubular
Excretion
Filtration pressure (energy from cardiac contraction) Excretion of solvent Nonprotein-bound molecules-charged uncharged Unidirectional
of the components then enables us to make fairly accurate predictions about the excretory patterns of a variety of molecules and, in a broad sense, to develop a set of rules that apply to the excretion of most drugs. I shall attempt, with this objective in mind, to describe the component forces involved in the renal tubular handling of drugs, and then to conclude the discussion with examples of work carried out in my laboratory on the renal tubular handling of mercurial diuretics-work that illustrates the complexity and variety of forces involved in renal excretion. GLOMERULAR AND PROXIMAL TUBULAR EXCRETION IN MAMMALS Entry of drugs into tubular urine occurs by means of glomerular filtration and, in many instances, by proximal tubular secretion. Some of the important features of these two mechanisms are compared in Table I. Although the energy for filtration is provided by the myocardium, that for tubular excretion is supplied by the renal cells. Glomerular filtration is unidirectional and permits entry of any dissociated or undissociated drug molecules that are not bound to plasma proteins. The drugs in solution are simply swept along together with fluid and other crystalloids (bulk-flow) through glomerular membranes which behave as though they were a sieve perforated by 75 to 100 A pores. The pores ordinarily are too small to permit the passage of much albumin, and virtually no globulin gets through. In contrast, proximal tubular transport is bidirectional. Organic acids, such as urate [l-3], para-aminohippurate [4], iodopyracet [ 51, m-hydroxybenzoate [6a] and taurocholate [6b], are both secreted and reabsorbed by carrier-mediated processes located in the proximal tubules. Protein binding appears to have very little effect on tubular secretion except in the case of substrates like phenol red which has a low affinity for the carriermediated transport system [7]. Although proximal tubular secretion involves the translocation of appropriate solutes, generally organic acids or bases, the possibility that water moves with the solute in mammals needs to be studied. The secretion pressure of the aglomerular kidney, the tubules of which correspond closely to the
in Mammals Transport
Oxidative metabolism (energy from proximal bular cells) Excretion of solute
tu-
Protein-bound or nonprotein-bound molecules generally charged Unidirectional or bidirectional
or
mammalian proximal tubule, may rise above the arterial pressure [ 81. It is interesting to note that Ludwig in 185 1 demonstrated that the pressure in the salivary duct of the dog can exceed that in the carotid artery by a considerable margin. Proximal tubular transport mechanisms have a limited capacity as do drug metabolizing systems in the liver. Glomerular filtration of a drug is not subject to this limitation. As the concentration of an unbound drug in plasma increases, the amount filtered increases linearly. Clearly, this is an advantageous situation with respect to the first step in elimination of the drug by the kidney. The capacity to excrete drugs is controlled by the glomerular filtration rate and in many instances by the ability of the proximal tubules to secrete them. These rates are not fixed; they vary throughout life. In the beginning, during the neonatal period, the functional capacity of the glomeruli and proximal tubules is improving: near the end, during the period of old age, capacity is deteriorating. Table II shows the differences.
TABLE II
Renal Excretion
of Drugs-Functional
Capacity Subject
Glomerular Filtration
Young infant
About 2 X 10bglomeruli filtering surface area related to glomerular volume u = TfD3/6
Young adult
Older adult
NOTE: rate.
April 1977
Proximal Tubular Secretion -____Lesser capacity than Young adult; can be induced
D z l/3 adult length GFR == 10 ml/min = 2 mllmin kg-’ About 2 X IO6 glomeruli GFR Z= 130 mlimin = 2 ml/min kg-’
Varies from drug to drug
(lean body mass) GFR decreases progressively from about age 60 to 50 per cent of the adult value (at age 80)
U = volume;
D = diameter;
GFR
Decreases progressively from age 50 to 50 per cent of the adult value (at age 80)
= glomerular
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filtration
491
RENAL TUBULAR HANDLING OF DRUGS-CAFRUNY
TABLE III
Acidic Drugs Secreted by Proximal Tubules*
Acetazolamide Hydrochlorothiazide Furosemide Ethacrynic acid Mersalyl Probenecid
TABLE IV
Spironolactone Sal icy lates Phenylbutazone Penicillins Cephaloridine Methotrexate
Procaine Morphine
[71 for more complete
* See Weiner
list and bibliography.
The neonate and the adult possess the same number of glomeruli, but the size of each set is different. Although measurements of the actual filtering surface of each glomerulus have not been made, it is clear that the filtering surface is proportional to the glomerular volume. The diameter of the glomeruli in neonates is about one-third that in young adults [9]. Since the volume of a sphere increases as the cube of its diameter, it is evident that a small increase in the diameter of the glomeruli will result in a much larger increase in glomerular volume. The smaller glomerular surface area in a young infant profoundly affects the filtration rate, and fortunately so. It is unlikely that infants, who normally possess the same number of glomeruli as the adult, could survive if these glomeruli were completely developed; the burden of reabsorption would be lntolerably excessive and the potential filtration rate would exceed the renal blood flow. In absolute terms, in the neonatal child the ability to filter drugs is less than that in adults, but when the dose is scaled downward appropriately these capacities are equivalent, the glomerular filtration rate factored by body weight being about 2.0 ml/min kg-’ in each case. In the neonate, the capacity of the kidney to secrete substances across the proximal tubule is similarly reduced [ 10,111; it is of great interest that, as with metabolizing systems in the liver, this function can be induced by exposing the kidnevs to transDortable molecules such as Denicillin [12]._ . Alas, the kidney does not retain its competence. Glomerular filtration and proximal tubular secretion [ 131 slow down in older adults, probably because of functional deterioration and structural changes. In healthy persons the reduced filtration rate does not lead to an increase in the serum concentration of creatinine, for the production of creatinine also diminishes [ 141. Tables Ill and IV provide a partial list of drugs known to be secreted by the proximal tubules. The list in Table III includes acidic drugs and drug metabolites; the substances in Table IV are all organic bases. The acid secretory system is exceedingly complex; it appears that there is more than one system or that branching pathways of a single system account for the fact that some
492
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The American Journal of Medicine
Pempidine Dopamine Neostigmine Quinine Thiamine
Histamine Tetraethylammonium Mecamylamine
Also drug metabolitesashippurates,glucuronides, etherealsulfates “See Weiner
Basic Drugs Secreted by Proximal Tubules*
Volume 62
[71 for more complete
list and bibliography.
competitive inhibitors of transport may be more effective than others depending on the substrate in question (see discussion [ 151). The organic base and organic acid transport systems appear to be mutually exclusive, but the transport of creatinine, a neutral substance, is blocked by inhibitors of both systems [ 16,171 and there is a surprising variation in its tubular handling by different species. It should be noted that most drugs are organic acids or bases. The failure of data to show that any given one is handled by proximal tubular secretion should not be accepted as definitive evidence that the drug is not secreted. The organic acid system appears to be bidirectional even for such notable substrates as para-aminohippuric acid. Although there have been valiant efforts to define the structural features of this system [ 18,191, no rules that have predictive value have emerged. REABSORPTION OF DRUGS Three processes govern the reabsorption of drugs from renal tubular lumens (Table V). The first is simple passive diffusion. The normal marked reduction in the volume of the glomerular filtrate, especially in the proximal tubule in which approximately two thirds of the filtrate is reabsorbed isosmotically, creates a large concentration gradient favoring the passive reabsorption of drug molecules. Movement of these molecules generally proceeds readily because the diffusible fraction (nonionized) of most organic drugs is sizable. Drug metabolites, on the other hand, are more polar and do not readily penetrate renal membranes despite favorable concentration gradients. The renal clearance of drugs that are reabsorbed largely by passive diffusion will generally display a linear relationship with urine flow rate. TABLE V
Reabsorption of Drugs
1. Simple passive diffusion 2. pH Dependent nonionic diffusion I + IO(PH~ - PK~) Acids: U/P = 1 + II$PHP - PK~) 1 + IO(PK~ -
Bases: U/P =
PHI)
1 + IO(PK~ - PHP)
3. Active transport -Amino acids, glucose, certain bile acids, other organic acids, chlormerodrin-cysteine, oxypurinol
RENAL TUBULAR HANDLING OF DRUGS--CAFRUNY
TABLE VI
The Rate of Renal Excretion of DrugsMajor Determining Factors
f2H5
IOPHENOXIC
Renal
Extrarenal
STRONGLY AND EXTENSIVELY BOUND TO PLASFiA PROTEIN
Renal blood flow Glomerular filtration rate Renal transport (secretorv and reabsorptivel
Plasma protein binding Total body water Hepatic biotransformation
ACID
SLOWLY
METABOLIZED
REABSORBED INTESTINE
IN
KIDNEY
AND
I
I
The renal excretion of organic acids that have pK values between 3.0 and 7.5 and bases with pK values between 7.5 and 10.5 is governed, often to a great extent, by urinary pH if the undissociated form is lipidsoluble. The equations describing the theoretic urine to plasma ratios that can develop at equilibrium are presented in Table V. The urinary excretion of such drugs as acetylsalicylic acid (pK = 3.5), phenobarbital (PK = 7.2) and probenecid (pK = 3.3) is enhanced considerably by procedures that increase urinary pH. The theoretic and practical aspects of this topic are discussed thoroughly by Milne [20] and Weiner and Mudge [21]. The active transport of drugs in a reabsorptive direction has not been studied very much even though a large volume of literature on this type of transport has accumulated (e.g., on sugars and amino acids). It appears that the reabsorptive transport of the cysteine adduct of chlormerodrin [22] and oxypurinol [23] is mediated. Each may be blocked by appropriate inhibitors, and it is probable that both are also secreted by the proximal tubules. RATE OF RENAL EXCRETION
OF DRUGS
The excretion rate of a drug expressed as a clearance value (Cd = udV/Pd where Cd = renal clearance of a drug, Ud and Pd = its urinary and plasma concentrations, and V = urine flow rate) varies over a wide range, approaching zero at one extreme and renal plasma flow at the other. The magnitude of the clearance depends, in part, on a number of physiologic variables. The major
TABLE VII
Effect of Extracellular Fluid Volume on Elimination Half-Life of lnulin Unit
Body weight (kg) Extracellular fluid volume (ml) Body weight f%) Glomerular filtration rate (mllmin) TX (min) where
Tt/
Young Infant
Adult
4.5 1.440 32 10 100
75.0 13,500 18 130 72
0.693 Vd = ~ GFR
NOTE: GFR = glomerular filtration rate. Vd = volume of distribution. Table modified from Rane and Wilson, Clinical Pharmacokinetics 1: 2, 1976.
4.
T1,2
(PLASMA)>
2,5
YEARS
Figure 7. fate of the cholecystographic agent, iophenoxic acid, in the body. t,,* = half-life in plasma.
variable factors are listed in Table VI. Plasma protein binding reduces the filtered fraction. Hepatic biotransformation accelerates the clearance in two ways: the acidic metabolites formed are usually secreted by the proximal tubules and, because they are often stronger acids than the original drug, are less lipid-soluble and, consequently, not readily reabsorbed. Renal clearance is also influenced by the size of the fluid compartments of the body. Table VII illustrates the effect of the extracellular fluid volume on the elimination half-life of inulin which is distributed in extracellular fluid. At a constant glomerular filtration rate, the amount of inulin delivered to the kidneys per unit time varies inversely with its volume of distribution. The half-life varies accordingly. This effect is prominent in young infants in whom the extracellular fluid volume is significantly larger than that in adults. The effect may be lessened in some cases because fractional protein binding is also less in infants than in adults [24,25]. Although binding to plasma proteins limits glomerular filtration, it does not always retard clearance. For example, the clearance of chlorothiazide, a compound secreted by the proximal tubules, approaches the renal plasma flow even though it is highly protein bound [26]. An example of a substance with a renal clearance near zero is iophenoxic acid (Figure 1). This watersoluble drug is strongly and extensively bound to plasma proteins, is slowly metabolized and is reabsorbed in both the kidney and the intestine [ 271. Its half-life in human plasma is at least two and a half years [28]. lophenoxic acid is thus a remarkable example of a water-soluble drug that the kidneys are unable to excrete. From the foregoing discussion, it is clear that the kidney is well equipped to handle offending chemicals. Its glomerular and proximal tubular excretory devices complement each other. When the function of one is limited by extraneous factors, the other takes over. The liver assists by processing drugs so that they can be excreted more readily by the kidney. Knowledge of
April 1977
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493
RENAL TUBULAR HANDLING OF DRUGS-CAFRUNY
Excretion of Mercury in the Aglomerular Fish, Lophius americanus
TABLE VIII
OCH3 H,N-%-NH-CH2-bH-CHzHg-Cl 0
Chlormerodrin Mersalyl Chlormerodrin Before the administration of Probenecid After the administration of Probenecid Merselyl Before the administration of Probenecid After the administration of Probenecid
CHLORMERODRIN
NOTE: Data from table of Cafruny to plasma.
Figure 2. Chemical structure of two mercurial diuretics, mersalyl and chlormerodrin. those factors that retard or enhance the renal excretion of drugs provides us with a set of flexible rules that have clinical application, especially in the design of dosage schedules in patients whose renal function is impaired, and in young infants and the aged whose renal capacities differ from that in the standard 70 kg male. OF MERCURIAL
I elected to discuss the renal tubular handling of mercurial diuretics to cap this report because many of the mechanisms and factors influencing the excretion of TABLE
IX
Renal Tubular
Experiments Standard
clearance
(dog) Stop-flow (dog)
Retrograde injection of chlormerodrin or chlormerodrin-cysteine into ureter with glucose as a marker Aglomerular fish (Lophius americanus)
April 1077
7ho Amorlccln
Results CHg:CT,
5
3
0.5 19.6
3
0.4 0.3
2 2
25.9 1.0
and Gussin [33].
of Chlormerodrin Conclusions
= 0.3-0.8
U/P Hg = 1.0-l U/P In
Probenecid es inhibitor-standard clearance (dog)
494
Handling
4
U/P = urine
drugs mentioned earlier come into play, and the discussion, therefore, comprises both an illustration and a summary of events. The mercurial diuretics are now rarely used, but they were onoe valuable drugs and their pharmacology has taught us a great deal. Although I shall refer only to mersalyl and chlormerodrin, it should be understood that ancillary data obtained with other mercurials are not in conflict with the results of studies of these two compounds. Strictly speaking, the data are not confirmatory, for the same types of experiments have not been carried out with a sufficient number of mercurials. Chlormerodrin and mersalyl are highly protein bound in plasma, yet both are excreted rapidly [29]. The amount of each filtered through the glomeruli must be exceedingly small, and data obtained with chlormerodrin seem to verify this premise [30]. Kessler et al. [3 1,321 obtained stop-flow patterns indicating that in the canine chlormerodrin was secreted by the proximal tubule. The
MERSALYL
THE RENAL TUBULAR HANDLING DIURETICS
No. Tested U/P Hg
Agent Tested
.6
at proximal peak Probenecid had no effect on proximal peak Slight increase in Hg clearance; Hg excretion increased by 40 per cent in 1 hour; renal Hg concentration declined from 40 to 10 UgIg cortex Loss of Hg from injected solution after chlormerodrin-cysteine; probenecid prevented loss Chlormerodrin: U/P Hg = 0.5; Mersalyl: U/P = 20.0; PAH: U/P = 25.0
Journal of Modlclno Volume 62
No evidence for secretion
Evidence for secretion of Hg Secretion
questionable
No evidence for secretion by acid transport system; possibly reabsorbed by this system
Chlormerodrin reabsorbed as a complex with cysteine; transport is via organic acid system Chlormerodrin creted
not se-
RENAL TUBULAR HANDLING OF DRUGS-CAFRUNY
secretory system did not appear to be the classic anion system. This fact is not surprising because the chlormerodrin molecule is neutral (Figure 2); mersalyl, on the other hand, is an acid. The renal concentration of these two mercurials differed by a wide margin, the levels of mersalyl at various times after the administration of a dose equivalent to 1 mg Hg/kg in the dog being about 10 pg/g of renal cortex and the value for chlormerodrin under comparable conditions about 45 pg/g [22,30]. In experiments similar to those of Kessler et al., the ratio of renal cortical mercury to plasma mercury varied from 15 to 42 after the administration of chlormerodrin and only from 1.6 to 1.8 after the administration of mersalyl [22]. From these data it seemed reasonable to suppose that chlormerodrin was not transported across the proximal tubule by an active or mediated process-that the stop-flow peak suggestive of this type of secretion was the result of a concentration gradient favoring the passive transfer of the drug from cells to lumens during the period of stopped-flow. Subsequent work [33] in the aglomerular fish (Table VIII) affirmed the notion that chlormerodrin was not secreted (UH9/PHS= 0.5, unchanged by probenecid) and provided the additional information that the organic acid,
mersalyl, was (Ur+s/PHS= 19.6, reduced to 1.O by probenecid). Mersalyl is secreted in the chicken [34]. Although it is claimed that chlormerodrin is also secreted in the chicken [35], the data are not clear-cut because the prevailing conditions of the experiments simulated those of stop-flow in the dog, in which passive flow in response to a concentration gradient could have accounted for the results. It is of interest parenthetically, that mersalyl has been found to be an extremely effective uricosuric agent in the chimpanzee [36]. The renal tubular handling of chlormerodrin is summarized in Table IX. The studies listed in the table support the following conclusions: (1) Large amounts of chlormerodrin are stored in renal cortical tissue. (2) It is transported in the proximal tubule by a carriermediated process inhibited by probenecid. (3) The direction of chlormerodrin transport is primarily from lumen to blood, but passive diffusion into urine occurs when a favorable cell-urine concentration gradient is established. (4) Mersalyl, a mercurial that possesses a carboxyl group, is transported primarily from blood to lumen by an organic acid secretory system.
REFERENCES 1. Mudge GH, Cucchi G, Platts M, et al.: Renal excretion of uric acid in the dog. Am J Physiol 215: 404, 1966. 2. Zins GR, Weiner IM: Bidirectional urate transport limited to the proximal tubule in dogs. Am J Physiol 215: 411, 1968. 3. Roth-Ramel F, Weiner IM: Excretion of urate by the kidneys of Cebus monkeys. A micropuncture study. Am J Physiol 224: 1369. 1973. 4. Cho KC, Cafruny EJ: Renal tubular reabsorption of p-aminohiopurate acid (PAH) in the dog. J Pharm Exp Ther 137: 1, 1970. 5. Kinter WB: Renal tubular transport of Diodrast-li3’ and PAH in Necturus: evidence for simultaneous reabsorption and secretion. Am J Physiol 196: 1141, 1959. 6. (a) May DG, Weiner IM: Bidirectional active transport of mhydroxybenzoate in proximal tubules of dogs. Am J Physiol 218: 430, 1970. (b) ZinsGR, Weiner,lM: Bidirectional transport of taurocholate by the proximal tubule of the dog. Am J Physiol215: 640, 1966. 7. Weiner IM: Transport of weak acids and bases. Handbook of Physiology, Renal Physiology (Berliner RW, Orloff J, eds), Washington, DC., American Physiological Society, 1970. a. Bieter RN: The secretion pressure of the aglomerular kidney. Am J Physiol 97: 66, 1931. 9. Fetterman GH, Shuplock NA, Philipp FJ, et al.: The growth and maturation of human glomeruli and proximal convolutions from term to adulthood. Pediatrics 35: 601, 1965. 10. Rennick B. Hamilton B, Evans R: Development of renal tubular transports of TEA and PAH in the puppy and piglet. Am J Physiol 201: 743, 1961. 11. Calcagno Pi-, Rubin Ml: Renal extraction of para-aminohippurate in infants and children. J Clin Invest 42: 1632, 1963.
12.
13.
14.
15.
16. 17.
ia. 19. 20. 21. 22.
23.
24.
April 1977
Hirsch GH, Hook JB: Maturation of renal organic acid transport: substrate stimulation by penicillin and p-aminohippurate (PAH). J Pharmacol Exp Ther 171: 103, 1970. Davies DF, Shock NW: Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest 29: 496, 1950. Kristensen M, Molholm Hansen J, Kampmann J, et al.: Drug elimination and renal function. J Clin Pharmacol 14: 307, 1974. Weiner IM, Fanelli GM Jr: Bidirectional transport: urate and other organic anions. Recent Advances in Renal physiology and Pharmacology (Wesson LG, Fanelli GM Jr, eds), Baltimore, University Park Press, 1974. O’Connell JMB, Romeo JA, Mudge GH: Renal tubular secretion of creatinine in the dog. Am J Physiol 203: 965, 1962. Swanson RE, Hakim AA: A stop-flow analysis of creatinine excretion in the dog. Am J Physiol 203: 960, 1962. Taggart JV: Mechanisms of renal tubular transport. Am J Med 24: 774, 1956. Despopolous A: A definition of substrate specificity in renal transport of organic ions. J Theoret Blol 6: 163, 1965. Milne MD: Influence of acid-base balance on efficacy and toxicity of drugs. Proc R Sot Med 58: 961, 1965. Weiner IM, Mudge GH: Renal tubular mechanisms for excretion of organic acids and bases. Am J Med 36: 743, 1964. Cafruny EJ: Reabsorptive transport of drugs. Renal Pharmacology (Fisher JW, Cafruny EJ, eds), New York, AppletonCentury-Crofts, 197 1. Elion GB, Yu TF, Gutman AB, et al.: Renal clearance of oxipurinol, the chief metabolite of Allopurinol. Am J Med 45: 69, 1966. Ehrnebo M, Agurell S, Jalling B, et al.: Age differences in drug binding by plasma proteins: studies on human foetuses, neonates and adults. Eur J Clin Pharmacol 3: 169, 1971.
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25. 26.
27.
28.
29. 30. 31.
496
Krasner J, Giacoia GP, Yaffe SJ: Drug-protein binding in the newborn infant. Ann NY Acad Sci 226: 101, 1973. Baer JE, Leidy HL, Brooks AV, et al.: The physiological disposition of chlorothiazide (Diuril) in the dog. J Pharmacol Exp Ther 125: 295, 1959. Mudge GH, Strewler GJ Jr, Desbiens N, et al.: Excretion and distribution of iophenoxic acid. J Pharmacol Exp Ther 178: 159,197l. Astwood EB: Occurrence in the sera of certain patients of large amounts of a newly isolated iodine compound. Assoc Am Physicians 70: 183, 1957. Cafruny EJ: The site and mechanism of action of mercurial diuretics. Pharmacol Rev 20: 89, 1968. Cafruny EJ, Cho KC, Gussin RZ: The pharmacology of mercurial diuretics. Ann NY Acad Sci 139: 362, 1966. Kessler RH. Hierholzer K, Gurd RS, et al.: Localization of diuretic action of chlormerodrin in the nephron of the dog.
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Journal of Medicine
Volume 62
32.
33.
34.
35.
36.
Am J Physiol 194: 540, 1958. Kessler RH, Lozano R, Pitts RF: Studies on structure diuretic activity relationships of organic compounds of mercury. J Clin Invest 36: 656, 1975. Cafruny EJ, Gussin RZ: Renal tubular excretion of mercurials in the aglomerular fish, Lophius americanus. J Pharmacol Exp Ther 155: 181, 1987. Weiner IM, Burnett AE, Rennick BR: The renal tubular secretion of mersalyl (Salyqan) in the chicken. J Pharmacol Exp Ther 118: 470, 1956. Campbell DES: Modification by bromcresol green or probenecid of the excretion and diuretic effect of three mercurial diuretics, diurgin R, chlormerodrin and mercumatilin. Acta Pharmacol Tox 17: 213, 1960. Fanelli GM Jr, Bohn DL, Reilly SS, et al.: Effects of mercurial diuretics on renal transport of urate in the chimpanzee. Am J Physiol 224: 985, 1973.
EDWARD J. CAFRUNY,
M.D., Ph.D.
New York, New York
From the Department of Pharmacology, Cornell University Medical College, New York, New York. Part of this study was supported by Grant AM13152 from the National Institutes of Health. Requests for reprints should be addressed to the Department of Pharmacology, Cornell University Medical College, 1300 York Avenue, New York, New York 10021.
490
April 1977
The renal excretion of drugs is a vectorial quantity, the resultant of physiologic mechanisms that have directtonal orientation and magnitude. Magnitude is limited by a variety of extrarenal factors including plasma protein binding and the volume of the total body water. The contributions of the glomeruli and tubules to excretion varies with age. This fact has clinical relevance, especially in newborn children and older patients. Although protein binding reduces the amount of a drug that can be filtered, it usually does not alter the rate of proximal tubular secretion of charged organic molecules. Reabsorption of the filtered fluid from tubular lumens creates concentration gradients favoring the reabsorption of drugs, but the movement of drug molecules out of luminal fluid is hindered by the formation of polar drug metabolites in the liver. Although there are only a few examples in the literature, it is probable that many drugs are reabsorbed by a carrier-mediated process located In the proximal tubules. A major difference exists between the renal handling of chlormerodrin, a neutral mercurial, and of mersalyl, an acidic mercurial. Chlormerodrin is reabsorbed (as a complex with cystelne) by a carrier-mediated process; mersalyl is secreted by one of the organic anion transport systems. Most of the useful information we possess on the renal tubular handling of drugs has been acquired in the last two decades, a period during which major advances in the development of analytical methods have been made. This information is still incomplete for each drug studied, and we continue to add new facts and figures. Much of the new data we are gathering have direct clinical application, and all careful studies in this field contribute to our understanding of renal function in health and disease. Any evaluation of the renal tubular handling of drugs hinges on an understanding of the forces involved in the operation of renal tubular transport mechanisms, for these forces apply to ali substances delivered to the kidney. The rate of excretion of any drug may be thought of as a vectorial quantity, the sum or resultant of a number of forces, each of which has magnitude and direction. Magnitude is dependent both on extrarenal factors (e.g., protein binding, drug metabolism, the force of cardiac contraction) and on renal forces (e.g., electrochemical gradients, active transport systems, urinary pH). Direction, on the other hand, is determined entirely by the structural components of the kidney which govern the orientation and capacity of its transporting functions. The sum or resultant vector applicable to the excretion of a number of drugs can be broken down into measurable components. Analysis
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Volume 62
RENAL TUBULAR HANDLING OF DRUGS--CAFRUNY
TABLE
I
Glomerular
Basic Feature Driving force
Primary orientation Solute characteristics Directional orientation
and Proximal Glomerular
Tubular
Excretion
Proximal Tubular
Excretion
Filtration pressure (energy from cardiac contraction) Excretion of solvent Nonprotein-bound molecules-charged uncharged Unidirectional
of the components then enables us to make fairly accurate predictions about the excretory patterns of a variety of molecules and, in a broad sense, to develop a set of rules that apply to the excretion of most drugs. I shall attempt, with this objective in mind, to describe the component forces involved in the renal tubular handling of drugs, and then to conclude the discussion with examples of work carried out in my laboratory on the renal tubular handling of mercurial diuretics-work that illustrates the complexity and variety of forces involved in renal excretion. GLOMERULAR AND PROXIMAL TUBULAR EXCRETION IN MAMMALS Entry of drugs into tubular urine occurs by means of glomerular filtration and, in many instances, by proximal tubular secretion. Some of the important features of these two mechanisms are compared in Table I. Although the energy for filtration is provided by the myocardium, that for tubular excretion is supplied by the renal cells. Glomerular filtration is unidirectional and permits entry of any dissociated or undissociated drug molecules that are not bound to plasma proteins. The drugs in solution are simply swept along together with fluid and other crystalloids (bulk-flow) through glomerular membranes which behave as though they were a sieve perforated by 75 to 100 A pores. The pores ordinarily are too small to permit the passage of much albumin, and virtually no globulin gets through. In contrast, proximal tubular transport is bidirectional. Organic acids, such as urate [l-3], para-aminohippurate [4], iodopyracet [ 51, m-hydroxybenzoate [6a] and taurocholate [6b], are both secreted and reabsorbed by carrier-mediated processes located in the proximal tubules. Protein binding appears to have very little effect on tubular secretion except in the case of substrates like phenol red which has a low affinity for the carriermediated transport system [7]. Although proximal tubular secretion involves the translocation of appropriate solutes, generally organic acids or bases, the possibility that water moves with the solute in mammals needs to be studied. The secretion pressure of the aglomerular kidney, the tubules of which correspond closely to the
in Mammals Transport
Oxidative metabolism (energy from proximal bular cells) Excretion of solute
tu-
Protein-bound or nonprotein-bound molecules generally charged Unidirectional or bidirectional
or
mammalian proximal tubule, may rise above the arterial pressure [ 81. It is interesting to note that Ludwig in 185 1 demonstrated that the pressure in the salivary duct of the dog can exceed that in the carotid artery by a considerable margin. Proximal tubular transport mechanisms have a limited capacity as do drug metabolizing systems in the liver. Glomerular filtration of a drug is not subject to this limitation. As the concentration of an unbound drug in plasma increases, the amount filtered increases linearly. Clearly, this is an advantageous situation with respect to the first step in elimination of the drug by the kidney. The capacity to excrete drugs is controlled by the glomerular filtration rate and in many instances by the ability of the proximal tubules to secrete them. These rates are not fixed; they vary throughout life. In the beginning, during the neonatal period, the functional capacity of the glomeruli and proximal tubules is improving: near the end, during the period of old age, capacity is deteriorating. Table II shows the differences.
TABLE II
Renal Excretion
of Drugs-Functional
Capacity Subject
Glomerular Filtration
Young infant
About 2 X 10bglomeruli filtering surface area related to glomerular volume u = TfD3/6
Young adult
Older adult
NOTE: rate.
April 1977
Proximal Tubular Secretion -____Lesser capacity than Young adult; can be induced
D z l/3 adult length GFR == 10 ml/min = 2 mllmin kg-’ About 2 X IO6 glomeruli GFR Z= 130 mlimin = 2 ml/min kg-’
Varies from drug to drug
(lean body mass) GFR decreases progressively from about age 60 to 50 per cent of the adult value (at age 80)
U = volume;
D = diameter;
GFR
Decreases progressively from age 50 to 50 per cent of the adult value (at age 80)
= glomerular
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491
RENAL TUBULAR HANDLING OF DRUGS-CAFRUNY
TABLE III
Acidic Drugs Secreted by Proximal Tubules*
Acetazolamide Hydrochlorothiazide Furosemide Ethacrynic acid Mersalyl Probenecid
TABLE IV
Spironolactone Sal icy lates Phenylbutazone Penicillins Cephaloridine Methotrexate
Procaine Morphine
[71 for more complete
* See Weiner
list and bibliography.
The neonate and the adult possess the same number of glomeruli, but the size of each set is different. Although measurements of the actual filtering surface of each glomerulus have not been made, it is clear that the filtering surface is proportional to the glomerular volume. The diameter of the glomeruli in neonates is about one-third that in young adults [9]. Since the volume of a sphere increases as the cube of its diameter, it is evident that a small increase in the diameter of the glomeruli will result in a much larger increase in glomerular volume. The smaller glomerular surface area in a young infant profoundly affects the filtration rate, and fortunately so. It is unlikely that infants, who normally possess the same number of glomeruli as the adult, could survive if these glomeruli were completely developed; the burden of reabsorption would be lntolerably excessive and the potential filtration rate would exceed the renal blood flow. In absolute terms, in the neonatal child the ability to filter drugs is less than that in adults, but when the dose is scaled downward appropriately these capacities are equivalent, the glomerular filtration rate factored by body weight being about 2.0 ml/min kg-’ in each case. In the neonate, the capacity of the kidney to secrete substances across the proximal tubule is similarly reduced [ 10,111; it is of great interest that, as with metabolizing systems in the liver, this function can be induced by exposing the kidnevs to transDortable molecules such as Denicillin [12]._ . Alas, the kidney does not retain its competence. Glomerular filtration and proximal tubular secretion [ 131 slow down in older adults, probably because of functional deterioration and structural changes. In healthy persons the reduced filtration rate does not lead to an increase in the serum concentration of creatinine, for the production of creatinine also diminishes [ 141. Tables Ill and IV provide a partial list of drugs known to be secreted by the proximal tubules. The list in Table III includes acidic drugs and drug metabolites; the substances in Table IV are all organic bases. The acid secretory system is exceedingly complex; it appears that there is more than one system or that branching pathways of a single system account for the fact that some
492
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The American Journal of Medicine
Pempidine Dopamine Neostigmine Quinine Thiamine
Histamine Tetraethylammonium Mecamylamine
Also drug metabolitesashippurates,glucuronides, etherealsulfates “See Weiner
Basic Drugs Secreted by Proximal Tubules*
Volume 62
[71 for more complete
list and bibliography.
competitive inhibitors of transport may be more effective than others depending on the substrate in question (see discussion [ 151). The organic base and organic acid transport systems appear to be mutually exclusive, but the transport of creatinine, a neutral substance, is blocked by inhibitors of both systems [ 16,171 and there is a surprising variation in its tubular handling by different species. It should be noted that most drugs are organic acids or bases. The failure of data to show that any given one is handled by proximal tubular secretion should not be accepted as definitive evidence that the drug is not secreted. The organic acid system appears to be bidirectional even for such notable substrates as para-aminohippuric acid. Although there have been valiant efforts to define the structural features of this system [ 18,191, no rules that have predictive value have emerged. REABSORPTION OF DRUGS Three processes govern the reabsorption of drugs from renal tubular lumens (Table V). The first is simple passive diffusion. The normal marked reduction in the volume of the glomerular filtrate, especially in the proximal tubule in which approximately two thirds of the filtrate is reabsorbed isosmotically, creates a large concentration gradient favoring the passive reabsorption of drug molecules. Movement of these molecules generally proceeds readily because the diffusible fraction (nonionized) of most organic drugs is sizable. Drug metabolites, on the other hand, are more polar and do not readily penetrate renal membranes despite favorable concentration gradients. The renal clearance of drugs that are reabsorbed largely by passive diffusion will generally display a linear relationship with urine flow rate. TABLE V
Reabsorption of Drugs
1. Simple passive diffusion 2. pH Dependent nonionic diffusion I + IO(PH~ - PK~) Acids: U/P = 1 + II$PHP - PK~) 1 + IO(PK~ -
Bases: U/P =
PHI)
1 + IO(PK~ - PHP)
3. Active transport -Amino acids, glucose, certain bile acids, other organic acids, chlormerodrin-cysteine, oxypurinol
RENAL TUBULAR HANDLING OF DRUGS--CAFRUNY
TABLE VI
The Rate of Renal Excretion of DrugsMajor Determining Factors
f2H5
IOPHENOXIC
Renal
Extrarenal
STRONGLY AND EXTENSIVELY BOUND TO PLASFiA PROTEIN
Renal blood flow Glomerular filtration rate Renal transport (secretorv and reabsorptivel
Plasma protein binding Total body water Hepatic biotransformation
ACID
SLOWLY
METABOLIZED
REABSORBED INTESTINE
IN
KIDNEY
AND
I
I
The renal excretion of organic acids that have pK values between 3.0 and 7.5 and bases with pK values between 7.5 and 10.5 is governed, often to a great extent, by urinary pH if the undissociated form is lipidsoluble. The equations describing the theoretic urine to plasma ratios that can develop at equilibrium are presented in Table V. The urinary excretion of such drugs as acetylsalicylic acid (pK = 3.5), phenobarbital (PK = 7.2) and probenecid (pK = 3.3) is enhanced considerably by procedures that increase urinary pH. The theoretic and practical aspects of this topic are discussed thoroughly by Milne [20] and Weiner and Mudge [21]. The active transport of drugs in a reabsorptive direction has not been studied very much even though a large volume of literature on this type of transport has accumulated (e.g., on sugars and amino acids). It appears that the reabsorptive transport of the cysteine adduct of chlormerodrin [22] and oxypurinol [23] is mediated. Each may be blocked by appropriate inhibitors, and it is probable that both are also secreted by the proximal tubules. RATE OF RENAL EXCRETION
OF DRUGS
The excretion rate of a drug expressed as a clearance value (Cd = udV/Pd where Cd = renal clearance of a drug, Ud and Pd = its urinary and plasma concentrations, and V = urine flow rate) varies over a wide range, approaching zero at one extreme and renal plasma flow at the other. The magnitude of the clearance depends, in part, on a number of physiologic variables. The major
TABLE VII
Effect of Extracellular Fluid Volume on Elimination Half-Life of lnulin Unit
Body weight (kg) Extracellular fluid volume (ml) Body weight f%) Glomerular filtration rate (mllmin) TX (min) where
Tt/
Young Infant
Adult
4.5 1.440 32 10 100
75.0 13,500 18 130 72
0.693 Vd = ~ GFR
NOTE: GFR = glomerular filtration rate. Vd = volume of distribution. Table modified from Rane and Wilson, Clinical Pharmacokinetics 1: 2, 1976.
4.
T1,2
(PLASMA)>
2,5
YEARS
Figure 7. fate of the cholecystographic agent, iophenoxic acid, in the body. t,,* = half-life in plasma.
variable factors are listed in Table VI. Plasma protein binding reduces the filtered fraction. Hepatic biotransformation accelerates the clearance in two ways: the acidic metabolites formed are usually secreted by the proximal tubules and, because they are often stronger acids than the original drug, are less lipid-soluble and, consequently, not readily reabsorbed. Renal clearance is also influenced by the size of the fluid compartments of the body. Table VII illustrates the effect of the extracellular fluid volume on the elimination half-life of inulin which is distributed in extracellular fluid. At a constant glomerular filtration rate, the amount of inulin delivered to the kidneys per unit time varies inversely with its volume of distribution. The half-life varies accordingly. This effect is prominent in young infants in whom the extracellular fluid volume is significantly larger than that in adults. The effect may be lessened in some cases because fractional protein binding is also less in infants than in adults [24,25]. Although binding to plasma proteins limits glomerular filtration, it does not always retard clearance. For example, the clearance of chlorothiazide, a compound secreted by the proximal tubules, approaches the renal plasma flow even though it is highly protein bound [26]. An example of a substance with a renal clearance near zero is iophenoxic acid (Figure 1). This watersoluble drug is strongly and extensively bound to plasma proteins, is slowly metabolized and is reabsorbed in both the kidney and the intestine [ 271. Its half-life in human plasma is at least two and a half years [28]. lophenoxic acid is thus a remarkable example of a water-soluble drug that the kidneys are unable to excrete. From the foregoing discussion, it is clear that the kidney is well equipped to handle offending chemicals. Its glomerular and proximal tubular excretory devices complement each other. When the function of one is limited by extraneous factors, the other takes over. The liver assists by processing drugs so that they can be excreted more readily by the kidney. Knowledge of
April 1977
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493
RENAL TUBULAR HANDLING OF DRUGS-CAFRUNY
Excretion of Mercury in the Aglomerular Fish, Lophius americanus
TABLE VIII
OCH3 H,N-%-NH-CH2-bH-CHzHg-Cl 0
Chlormerodrin Mersalyl Chlormerodrin Before the administration of Probenecid After the administration of Probenecid Merselyl Before the administration of Probenecid After the administration of Probenecid
CHLORMERODRIN
NOTE: Data from table of Cafruny to plasma.
Figure 2. Chemical structure of two mercurial diuretics, mersalyl and chlormerodrin. those factors that retard or enhance the renal excretion of drugs provides us with a set of flexible rules that have clinical application, especially in the design of dosage schedules in patients whose renal function is impaired, and in young infants and the aged whose renal capacities differ from that in the standard 70 kg male. OF MERCURIAL
I elected to discuss the renal tubular handling of mercurial diuretics to cap this report because many of the mechanisms and factors influencing the excretion of TABLE
IX
Renal Tubular
Experiments Standard
clearance
(dog) Stop-flow (dog)
Retrograde injection of chlormerodrin or chlormerodrin-cysteine into ureter with glucose as a marker Aglomerular fish (Lophius americanus)
April 1077
7ho Amorlccln
Results CHg:CT,
5
3
0.5 19.6
3
0.4 0.3
2 2
25.9 1.0
and Gussin [33].
of Chlormerodrin Conclusions
= 0.3-0.8
U/P Hg = 1.0-l U/P In
Probenecid es inhibitor-standard clearance (dog)
494
Handling
4
U/P = urine
drugs mentioned earlier come into play, and the discussion, therefore, comprises both an illustration and a summary of events. The mercurial diuretics are now rarely used, but they were onoe valuable drugs and their pharmacology has taught us a great deal. Although I shall refer only to mersalyl and chlormerodrin, it should be understood that ancillary data obtained with other mercurials are not in conflict with the results of studies of these two compounds. Strictly speaking, the data are not confirmatory, for the same types of experiments have not been carried out with a sufficient number of mercurials. Chlormerodrin and mersalyl are highly protein bound in plasma, yet both are excreted rapidly [29]. The amount of each filtered through the glomeruli must be exceedingly small, and data obtained with chlormerodrin seem to verify this premise [30]. Kessler et al. [3 1,321 obtained stop-flow patterns indicating that in the canine chlormerodrin was secreted by the proximal tubule. The
MERSALYL
THE RENAL TUBULAR HANDLING DIURETICS
No. Tested U/P Hg
Agent Tested
.6
at proximal peak Probenecid had no effect on proximal peak Slight increase in Hg clearance; Hg excretion increased by 40 per cent in 1 hour; renal Hg concentration declined from 40 to 10 UgIg cortex Loss of Hg from injected solution after chlormerodrin-cysteine; probenecid prevented loss Chlormerodrin: U/P Hg = 0.5; Mersalyl: U/P = 20.0; PAH: U/P = 25.0
Journal of Modlclno Volume 62
No evidence for secretion
Evidence for secretion of Hg Secretion
questionable
No evidence for secretion by acid transport system; possibly reabsorbed by this system
Chlormerodrin reabsorbed as a complex with cysteine; transport is via organic acid system Chlormerodrin creted
not se-
RENAL TUBULAR HANDLING OF DRUGS-CAFRUNY
secretory system did not appear to be the classic anion system. This fact is not surprising because the chlormerodrin molecule is neutral (Figure 2); mersalyl, on the other hand, is an acid. The renal concentration of these two mercurials differed by a wide margin, the levels of mersalyl at various times after the administration of a dose equivalent to 1 mg Hg/kg in the dog being about 10 pg/g of renal cortex and the value for chlormerodrin under comparable conditions about 45 pg/g [22,30]. In experiments similar to those of Kessler et al., the ratio of renal cortical mercury to plasma mercury varied from 15 to 42 after the administration of chlormerodrin and only from 1.6 to 1.8 after the administration of mersalyl [22]. From these data it seemed reasonable to suppose that chlormerodrin was not transported across the proximal tubule by an active or mediated process-that the stop-flow peak suggestive of this type of secretion was the result of a concentration gradient favoring the passive transfer of the drug from cells to lumens during the period of stopped-flow. Subsequent work [33] in the aglomerular fish (Table VIII) affirmed the notion that chlormerodrin was not secreted (UH9/PHS= 0.5, unchanged by probenecid) and provided the additional information that the organic acid,
mersalyl, was (Ur+s/PHS= 19.6, reduced to 1.O by probenecid). Mersalyl is secreted in the chicken [34]. Although it is claimed that chlormerodrin is also secreted in the chicken [35], the data are not clear-cut because the prevailing conditions of the experiments simulated those of stop-flow in the dog, in which passive flow in response to a concentration gradient could have accounted for the results. It is of interest parenthetically, that mersalyl has been found to be an extremely effective uricosuric agent in the chimpanzee [36]. The renal tubular handling of chlormerodrin is summarized in Table IX. The studies listed in the table support the following conclusions: (1) Large amounts of chlormerodrin are stored in renal cortical tissue. (2) It is transported in the proximal tubule by a carriermediated process inhibited by probenecid. (3) The direction of chlormerodrin transport is primarily from lumen to blood, but passive diffusion into urine occurs when a favorable cell-urine concentration gradient is established. (4) Mersalyl, a mercurial that possesses a carboxyl group, is transported primarily from blood to lumen by an organic acid secretory system.
REFERENCES 1. Mudge GH, Cucchi G, Platts M, et al.: Renal excretion of uric acid in the dog. Am J Physiol 215: 404, 1966. 2. Zins GR, Weiner IM: Bidirectional urate transport limited to the proximal tubule in dogs. Am J Physiol 215: 411, 1968. 3. Roth-Ramel F, Weiner IM: Excretion of urate by the kidneys of Cebus monkeys. A micropuncture study. Am J Physiol 224: 1369. 1973. 4. Cho KC, Cafruny EJ: Renal tubular reabsorption of p-aminohiopurate acid (PAH) in the dog. J Pharm Exp Ther 137: 1, 1970. 5. Kinter WB: Renal tubular transport of Diodrast-li3’ and PAH in Necturus: evidence for simultaneous reabsorption and secretion. Am J Physiol 196: 1141, 1959. 6. (a) May DG, Weiner IM: Bidirectional active transport of mhydroxybenzoate in proximal tubules of dogs. Am J Physiol 218: 430, 1970. (b) ZinsGR, Weiner,lM: Bidirectional transport of taurocholate by the proximal tubule of the dog. Am J Physiol215: 640, 1966. 7. Weiner IM: Transport of weak acids and bases. Handbook of Physiology, Renal Physiology (Berliner RW, Orloff J, eds), Washington, DC., American Physiological Society, 1970. a. Bieter RN: The secretion pressure of the aglomerular kidney. Am J Physiol 97: 66, 1931. 9. Fetterman GH, Shuplock NA, Philipp FJ, et al.: The growth and maturation of human glomeruli and proximal convolutions from term to adulthood. Pediatrics 35: 601, 1965. 10. Rennick B. Hamilton B, Evans R: Development of renal tubular transports of TEA and PAH in the puppy and piglet. Am J Physiol 201: 743, 1961. 11. Calcagno Pi-, Rubin Ml: Renal extraction of para-aminohippurate in infants and children. J Clin Invest 42: 1632, 1963.
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Hirsch GH, Hook JB: Maturation of renal organic acid transport: substrate stimulation by penicillin and p-aminohippurate (PAH). J Pharmacol Exp Ther 171: 103, 1970. Davies DF, Shock NW: Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest 29: 496, 1950. Kristensen M, Molholm Hansen J, Kampmann J, et al.: Drug elimination and renal function. J Clin Pharmacol 14: 307, 1974. Weiner IM, Fanelli GM Jr: Bidirectional transport: urate and other organic anions. Recent Advances in Renal physiology and Pharmacology (Wesson LG, Fanelli GM Jr, eds), Baltimore, University Park Press, 1974. O’Connell JMB, Romeo JA, Mudge GH: Renal tubular secretion of creatinine in the dog. Am J Physiol 203: 965, 1962. Swanson RE, Hakim AA: A stop-flow analysis of creatinine excretion in the dog. Am J Physiol 203: 960, 1962. Taggart JV: Mechanisms of renal tubular transport. Am J Med 24: 774, 1956. Despopolous A: A definition of substrate specificity in renal transport of organic ions. J Theoret Blol 6: 163, 1965. Milne MD: Influence of acid-base balance on efficacy and toxicity of drugs. Proc R Sot Med 58: 961, 1965. Weiner IM, Mudge GH: Renal tubular mechanisms for excretion of organic acids and bases. Am J Med 36: 743, 1964. Cafruny EJ: Reabsorptive transport of drugs. Renal Pharmacology (Fisher JW, Cafruny EJ, eds), New York, AppletonCentury-Crofts, 197 1. Elion GB, Yu TF, Gutman AB, et al.: Renal clearance of oxipurinol, the chief metabolite of Allopurinol. Am J Med 45: 69, 1966. Ehrnebo M, Agurell S, Jalling B, et al.: Age differences in drug binding by plasma proteins: studies on human foetuses, neonates and adults. Eur J Clin Pharmacol 3: 169, 1971.
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25. 26.
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28.
29. 30. 31.
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Krasner J, Giacoia GP, Yaffe SJ: Drug-protein binding in the newborn infant. Ann NY Acad Sci 226: 101, 1973. Baer JE, Leidy HL, Brooks AV, et al.: The physiological disposition of chlorothiazide (Diuril) in the dog. J Pharmacol Exp Ther 125: 295, 1959. Mudge GH, Strewler GJ Jr, Desbiens N, et al.: Excretion and distribution of iophenoxic acid. J Pharmacol Exp Ther 178: 159,197l. Astwood EB: Occurrence in the sera of certain patients of large amounts of a newly isolated iodine compound. Assoc Am Physicians 70: 183, 1957. Cafruny EJ: The site and mechanism of action of mercurial diuretics. Pharmacol Rev 20: 89, 1968. Cafruny EJ, Cho KC, Gussin RZ: The pharmacology of mercurial diuretics. Ann NY Acad Sci 139: 362, 1966. Kessler RH. Hierholzer K, Gurd RS, et al.: Localization of diuretic action of chlormerodrin in the nephron of the dog.
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Am J Physiol 194: 540, 1958. Kessler RH, Lozano R, Pitts RF: Studies on structure diuretic activity relationships of organic compounds of mercury. J Clin Invest 36: 656, 1975. Cafruny EJ, Gussin RZ: Renal tubular excretion of mercurials in the aglomerular fish, Lophius americanus. J Pharmacol Exp Ther 155: 181, 1987. Weiner IM, Burnett AE, Rennick BR: The renal tubular secretion of mersalyl (Salyqan) in the chicken. J Pharmacol Exp Ther 118: 470, 1956. Campbell DES: Modification by bromcresol green or probenecid of the excretion and diuretic effect of three mercurial diuretics, diurgin R, chlormerodrin and mercumatilin. Acta Pharmacol Tox 17: 213, 1960. Fanelli GM Jr, Bohn DL, Reilly SS, et al.: Effects of mercurial diuretics on renal transport of urate in the chimpanzee. Am J Physiol 224: 985, 1973.
