Gen. Pharmae., 1976, Vol. 7, pP. I to 4. Pergamon Press. Prlnted tn Great Britain
MINIREVIEW COMPARATIVE PHARMACOLOGY OF URICOSURIC DRUGS I. M. W ~ g
Department of Pharmacology, State University of New York, Upstate Medical Center, Syracuse, NY 13210, U.S.A. (Received 22 July 1975) Fifteen years ago Gutman and Yii proposed a model for the renal disposition of urate in man which included filtration of urate at the glomerulus, tubular secretion of urate by a process which is inhibitable by drugs and tubular reabsorption by a mechanism which is also inhibitable by drugs. The model was based on an ingenuous interpretation of pharmacological experiments. In man of the two transtubular processes, re,absorption normally dominates, i.e. only a small fraction of the urate which enters the tubules is excreted. Uricosuric drugs are thought to inhibit the reabsorptive mechanism selectively or at least to a greater extent than the secretory mechanism and thereby increase the fractional excretion of urate. For the most part the uricosuric activities of drugs have been discovered incidentally to their clinical use for other activities. This phenomenon stems in part from the lack (until recently) of suitable animal models for the demonstration of uricosuric action. Recent studies on the comparative physiology and pharmacology of urate excretion have provided some useful animal models and in addition have provided further support for the three component model proposed by Gutman and Yii, i.e. the model seems generally applicable in a wide variety of species. Of all the animals extensively studied, including man, the chimpanzee, Pan troglodytes, gives the most intense and consistent response to the greatest variety of drugs. This discovery was made by G. M. Fanelli, Jr. who also observed that the overall pattern for urate excretion in the chimpanzee and drug effects thereon were qualitatively similar to those in man. The foregoing factors make the chimpanzee a convenient starting point for consideration of comparative pharmacology. In this analysis I make t h e assumption that drugs act directly only to inhibit transport processes; I know of no evidence with the urate system to suggest otherwise. In the plasma of chimpanzees; urate is sparingly bound to macromolecules and is therefore largely filterable at the glomerulus. Consequently, the rate at which urate is filtered is in the main determined by the concentration of urate in plasma and those
factors which determine the rate of fluid filtration. The urinary excretion of urate is some 10yo the quantity filtered, i.e. ca. 90% of filtered urate appears to be reabsorbed by the renal tubules. This fractional net reabsorption of urate can be increased by drugs, notably pyrazinamide or pyrazinoic acid, the active metabolite of pyrazinamide. There is good evidence in other species (dog, Cebus monkey and rat) that pyrazinoate inhibits a secretory flux of urate and thus it seems clear that the urate which appears in the urine is derived from and represents a small fraction of a quantity which gained access to the tubular urine by both secretion and filtration. The existence of the secretory flux for urate in the chimpanzee is dramatically demonstrated by the administration of the mercurial diuretic, mersalyl, which presumably inhibits the reabsorptive process. After the latter drug is given, net secretion of urate is observed, i.e. the rate of urate excretion exceeds the rate at which it is filtered. Thus the transport of urate across the tubular epithelium is bidirectional and both the secretory and reabsorptive transports are susceptible to inhibition by drugs. It is probable that both transport processes are examples of active (uphill) transport. After pyrazinoate administration the concentration of urate in urine may be much lower than in plasma. The net secretion of urate (an anion) seen after mersalyl injection can hardly be explained by any mechanism other than active transport. The foregoing description of the disposition of urate in the chimpanzee kidney is in general similar to that deduced by the human kidney and the kidney of the New World monkeys in the genus, Cebus. In all three species the quantity of urate excreted is a small fraction of that filtered and in all three there is evidence for tubular secretion of urate. However, there are important quantitative differences in the responses to drugs. The chimpanzee is most sensitive to uricosuric drugs, man is next and Cebus monkeys are relatively unresponsive. There is a major proble~ in analyzing these differing degrees of responsiveness to uricosuric drugs. The problem stems from the fact that some, perhaps all, of the drugs which influence urate excretion may have simultaneous effects on both 1
2
I.M. WEINER
secretion and reabsorption. F o r example, in the chimpanzee, pyrazinoate at low doses causes urate retention, i.e. it inhibits mainly secretion; but at high doses the drug is uricosuric, i.e. an effect on reabsorption becomes prominent. A t the present time we cannot be certain that the inhibition o f urate secretion seen with low doses is a "pure" effect. There may indeed be simultaneous inhibition o f reabsorption, albeit of smaller magnitude. As a consequence of these considerations one is at a loss as to whether to ascribe lesser responsiveness to uricosuric drugs to a decreased sensitivity of the reabsorptive mechanism or to an increased sensitivity of the urate secretory mechanism. Thus far I have considered species in which the net movement of urate is in the reabsorptive direction. Other animals in this category are the dog (except for the Dalmatian Coach Hound), cat and rat. On the other hand, there are animals in which secretion is the dominant process. In the latter category are birds, reptiles, Dalmatian Coach Hounds, guinea pigs and various species of monkeys. It is of considerable interest that drugs which are uricosuric in man often cause urate retention in the latter animals. In retrospect such findings are not surprising in light of the fact that many drugs have the ability to inhibit both secretion and reabsorption. All other things being equal, it is obvious that inhibition of the more prominent system will have the dominant effect on excretion. The rabbit is not easily placed in either of the foregoing categories. Depending on experimental conditions (and probably individual variation) either net secretion or reabsorption is seen. In some instances when the dominant transport system is impeded by drugs or other measures net transport in the opposite direction is observed. This is presumably a consequence of bidirectional urate transport. Considerable effort has been expanded in determining the intrarenal sites of urate transport and thus the sites of drug action. Much of the work has been done with the stop-flow technique. In the mongrel dog, cat, rabbit and Cebus monkey normal net reabsorption has been assigned to the proximal tubule. In the dog and Cebus the major site of urate secretion is also the proximal tubule. In animals that normally show net secretion, the results of stop--flow experiments indicate that secretion occurs in the proximal tubules of Dalmatian Coach Hounds, rabbits, guinea pigs and goats. More precise localizations have been made with mieropuncture and related technique in a few instances. In Cebus both the secretory and reabsorptive fluxes seem to be largely coextensive in the proximal convoluted tubule. In rabbits net reabsorption predominates in the proximal convolution (although bidirectional transport probably occurs there) and net secretion in the latter part of the proximal tubule (the straight part of pars recta). A similar situation obtains in
the Dalmatian Coach Hound. In rats there is obviously bidirectional transport in the proximal convolutions but the direction o f net transport in this segment and the importance o f later segments is still debated. I favor the view that the rat resembles Cebus in this context. In snakes net urate secretion occurs throughout the proximal tubule. It may be important that in the two mammals which secrete urate and which have been studied with microtechniques, that net urate secretion occurs in the pars recta. This may explain why inhibitors of secretion uncover only modest net reabsorption, i.e. the major reabsorptive site is proximal to the major secretory site. In other animals in which secretion and reabsorption are more nearly coextensive, inhibitors of secretion may have much more profound effects, e.g. man, chimpanzee. There is evidence in snakes, dogs, monkeys and chimpanzees that the secretory mechanism for urate is distinct from that for other organic anions such as p-aminohippurate, although both processes occur in the same nephron segments. However, the specificity of the two secretory mechanisms is not great and in mammals at least, inhibitors of one system often inhibit the other. In the following paragraphs I will summarize briefly the drug effects in the various non-human species for which there is substantial information. Because of insufficient information it will not be possible to take into account the effects of differing plasma concentrations of urate in the various animals and various experimental settings. It will be remembered that the tissues of most mammals (except man and great apes) contain the enzyme, uricase, which keeps the level of urate in the circulation very low. In many of the experiments in the literature urate has been infused to elevate urate levels in part for analytical convenience.
Chimpanzee The general pattern of urate excretion has already been described. Probenecid, a probenecid derivative (2-nitroprobenecid), sulfinpyrazone, zoxazolamine, salicylate, carinamide, iodopyracet, chlorothiazide (acutely), halofenate and mersalyl are all uricosuric in this animal. All of the foregoing substances are also uricosuric in man. In general, the intensity of uricosuria with any given dose seems greater in the chimpanzee than in man. This difference has been specifically confirmed with salicylate, probeneeid and mersalyl. Pyrazinoate depresses urate excretion and prevents the uricosuric response to some but not all o f the foregoing drugs. Pyrazinoate reduces the uricosuric response to most o f the remaining drugs. Pyrazinoate in very large doses is uricosurie. Cebus monkeys The general pattern of urate excretion is similar to that of the chimpanzee and man. Probenecid,
Comparative pharmacology of uricosuric drugs 2-substituted probenecid derivatives, sulfmpyrazone, benziodarone, phenylbutazone, salicylate, iodopyracet, mersalyl, and chlorothiazide (acutely) are uricosuric; zoxazolamine at the doses tested was not. In general the uricosuric responses are inferior to those observed in man. Pyrazinoate depresses urate excretion and has been shown to depress the uricosurie responses to some of the foregoing drugs. Nicotinic acid, m-hydroxybenzoic acid and 2,4dinitrophenol also depress urate excretion. Pyrazinoate in very large doses is uricosurie. As noted previously this is the only primate for which there are data from micropuncture studies.
Dogs In non-Dalmatian dogs urate reabsorption predominates over secretion and both processes occur in the proximal tubule. In general drug effects are very difficult to observe. One gains the impression that drug effects are somewhat more easily demonstrable when studies are conducted at endogenous levels of urate. Probenecid and probenecid derivatives exert slight uricosuric actions, as does ouabain. Pyrazinoate in large doses is uricosuric but at lower doses has no effect on overall urate excretion. However, very small amounts of pyrazinoate and other substances definitely suppress the secretory process when the latter is specifically studied. It may well be that both secretion and reabsorption are inhibited to approximately equal extents by drugs and that this accounts for the lack of easily appreciated changes in net secretion. In the Dalmatian Coach Hound (net secretion of urate) substances which are ordinarily uricosuric in man tend to decrease urate excretion as does pyrazinoamide. In some instances inhibitors of secretion uncover net reabsorption. Rabbit These animals may demonstrate either net secretion or net re,absorption of urate. Both processes occur in the proximal tubule, although secretion predominates in the pars recta. In some studies net secretion has been correlated with elevated levels of plasma urate or with intensity of osmotic diuresis. When secretion occurs it is depressed by probenecid. The following have been shown to depress re,absorption in stop--flow experiments: ehlorothiazide, lactate, creatinine and pyrazinoate. Guinea pig The majority of specimens demonstrate net secretion o f urate which occurs in the proximal tubule. Net secretion is inhibited by probenecid and converted to net reabsorption (also a proximal tubular process). Pyrazinoate causes a modest inhibition of secretion. Chlorothiazide and ouabaln had minimal activities. Rat Clearance studies demonstrate overall net rcabsorption of urate. It is not yet entirely clear which
is the net direction of urate transport in the proximal convolutions although the weight of the evidence favours reabsorption. There is, however, general agreement that bidirectional transport occurs in the proximal tubule. Probenecid has a substantial uricosuric effect when plasma urate is low and a modest effect when plasma urate is elevated. On the other hand pyrazinamide (andp-aminohippurate) depressed urate excretion when plasma level of urate was high, but the effect at lower levels of urate was modest. In microinjection experiments the reabsorptive flux of urate was inhibited by p-aminohippurate, probenecid and pyrazinoate. Definite evidence for the inhibition of the secretory flux by pyrazinoate is also available. Hydrochlorothiazide and sulfinpyrazone have no effect on net excretion in acute experiments, although an indirect action of thiazides has been demonstrated, i.e. urate excretion was depressed secondary to volume depletion.
Chicken There is extensive net secretion of urate in this species. Probenecid, sulfinpyrazone, zoxazolamine, phenylbutazone, p-aminohippurate, chlorothiazide, salicylate and 2,4-dinitrophenol have been shown to depress urate secretion. Pyrazinamide was ineffective in two studies, but it is not known whether or not it was converted to the active metabolite, pyrazinoate. It appeared for a time that all drugs which acted on urate excretion in the chicken depressed secretion, i.e. there was no evidence for reabsorption. However, Quebbemann and his colleagues have recently demonstrated that ethacrynic acid and furosemide cause considerable enlaancement of urate excretion. They suggest that the latter drugs inhibit a reabsorptive process. Snakes The snake (Natrix and Thamnophis spp.) demonstrates net secretion of urate which occurs in proximal tubules. The evidence is clear that the active transport step in secretion occurs at the basilar membrane of the tubular cell. There is also a re,absorptive flux of urate in proximal tubules; the evidence currently available suggests that this flux is passive. Should the latter be true it would represent a marked difference from certain mammals. The evidence that urate and p-aminohippurate are secreted by separate mechanisms is convincing. Both secretory mechanisms are inhibited by probenecid. The Hterature Two recent, extensive reviews are available (Mudge et al., 1973; Gutman & Yi, 1972). In addition, much of the more recent literature has been covered by Lassiter (1975) and also appears in a symposium issue of Nephron (Rieselbach & Steele, 1975). Danzler's elegant work on the snake kidney can be traced through a recent paper
4
I . M . WEINER
(Dantzler, 1974). Fanelli & Beyer have provided a comprehensive review of urate disposition in nonhuman primates (Fanelli & Beyer, 1974). Unfortunately, a substantial amount of material included in this paper has been gathered from recent abstracts and personal communications concerning papers in press.
REFERENCES
Mtrr~E G. H.,BErtNDTW. O. &VALTENH. (1973) Tubular transport of urea, glucose, phosphate, uric acid, sulfate and thiosulfate. In Handbook of Physiology, Section 8, Renal Physiology (Edited by ORLOFr J. & B~RLINER
R. W. pp. 587-652. American Physiological Society, Washington, D.C. GUTMANA. B. & Yt~ T. F. (1972) Renal mechanisms for regulation of uric acid secretion, with special reference to normal and gouty men. Sere. Arthritis Rheum. 2, I--46. LASSITER W. E. (1975) Kidney. Ann. Rev. Physiol. 37, 371-393. RIESELBACHR. E. & STEELET. n . (Editors) (1975) Symposium on the influence of the kidney upon urate homeostasis in man. Nephron 14, 1-116. DANZLERW. H. (1974) PAH transport by snake proximal renal tubules: differences from urate transport. Am. J. Physiol. 226, 634-641. FANELLIG. M. Jr., & BEYERK. H. Jr. (1974) Uric acid in nonhuman primates with special reference to its renal transport. Ann. Rev. Pharmacol. 14, 355-364.
MINIREVIEW COMPARATIVE PHARMACOLOGY OF URICOSURIC DRUGS I. M. W ~ g
Department of Pharmacology, State University of New York, Upstate Medical Center, Syracuse, NY 13210, U.S.A. (Received 22 July 1975) Fifteen years ago Gutman and Yii proposed a model for the renal disposition of urate in man which included filtration of urate at the glomerulus, tubular secretion of urate by a process which is inhibitable by drugs and tubular reabsorption by a mechanism which is also inhibitable by drugs. The model was based on an ingenuous interpretation of pharmacological experiments. In man of the two transtubular processes, re,absorption normally dominates, i.e. only a small fraction of the urate which enters the tubules is excreted. Uricosuric drugs are thought to inhibit the reabsorptive mechanism selectively or at least to a greater extent than the secretory mechanism and thereby increase the fractional excretion of urate. For the most part the uricosuric activities of drugs have been discovered incidentally to their clinical use for other activities. This phenomenon stems in part from the lack (until recently) of suitable animal models for the demonstration of uricosuric action. Recent studies on the comparative physiology and pharmacology of urate excretion have provided some useful animal models and in addition have provided further support for the three component model proposed by Gutman and Yii, i.e. the model seems generally applicable in a wide variety of species. Of all the animals extensively studied, including man, the chimpanzee, Pan troglodytes, gives the most intense and consistent response to the greatest variety of drugs. This discovery was made by G. M. Fanelli, Jr. who also observed that the overall pattern for urate excretion in the chimpanzee and drug effects thereon were qualitatively similar to those in man. The foregoing factors make the chimpanzee a convenient starting point for consideration of comparative pharmacology. In this analysis I make t h e assumption that drugs act directly only to inhibit transport processes; I know of no evidence with the urate system to suggest otherwise. In the plasma of chimpanzees; urate is sparingly bound to macromolecules and is therefore largely filterable at the glomerulus. Consequently, the rate at which urate is filtered is in the main determined by the concentration of urate in plasma and those
factors which determine the rate of fluid filtration. The urinary excretion of urate is some 10yo the quantity filtered, i.e. ca. 90% of filtered urate appears to be reabsorbed by the renal tubules. This fractional net reabsorption of urate can be increased by drugs, notably pyrazinamide or pyrazinoic acid, the active metabolite of pyrazinamide. There is good evidence in other species (dog, Cebus monkey and rat) that pyrazinoate inhibits a secretory flux of urate and thus it seems clear that the urate which appears in the urine is derived from and represents a small fraction of a quantity which gained access to the tubular urine by both secretion and filtration. The existence of the secretory flux for urate in the chimpanzee is dramatically demonstrated by the administration of the mercurial diuretic, mersalyl, which presumably inhibits the reabsorptive process. After the latter drug is given, net secretion of urate is observed, i.e. the rate of urate excretion exceeds the rate at which it is filtered. Thus the transport of urate across the tubular epithelium is bidirectional and both the secretory and reabsorptive transports are susceptible to inhibition by drugs. It is probable that both transport processes are examples of active (uphill) transport. After pyrazinoate administration the concentration of urate in urine may be much lower than in plasma. The net secretion of urate (an anion) seen after mersalyl injection can hardly be explained by any mechanism other than active transport. The foregoing description of the disposition of urate in the chimpanzee kidney is in general similar to that deduced by the human kidney and the kidney of the New World monkeys in the genus, Cebus. In all three species the quantity of urate excreted is a small fraction of that filtered and in all three there is evidence for tubular secretion of urate. However, there are important quantitative differences in the responses to drugs. The chimpanzee is most sensitive to uricosuric drugs, man is next and Cebus monkeys are relatively unresponsive. There is a major proble~ in analyzing these differing degrees of responsiveness to uricosuric drugs. The problem stems from the fact that some, perhaps all, of the drugs which influence urate excretion may have simultaneous effects on both 1
2
I.M. WEINER
secretion and reabsorption. F o r example, in the chimpanzee, pyrazinoate at low doses causes urate retention, i.e. it inhibits mainly secretion; but at high doses the drug is uricosuric, i.e. an effect on reabsorption becomes prominent. A t the present time we cannot be certain that the inhibition o f urate secretion seen with low doses is a "pure" effect. There may indeed be simultaneous inhibition o f reabsorption, albeit of smaller magnitude. As a consequence of these considerations one is at a loss as to whether to ascribe lesser responsiveness to uricosuric drugs to a decreased sensitivity of the reabsorptive mechanism or to an increased sensitivity of the urate secretory mechanism. Thus far I have considered species in which the net movement of urate is in the reabsorptive direction. Other animals in this category are the dog (except for the Dalmatian Coach Hound), cat and rat. On the other hand, there are animals in which secretion is the dominant process. In the latter category are birds, reptiles, Dalmatian Coach Hounds, guinea pigs and various species of monkeys. It is of considerable interest that drugs which are uricosuric in man often cause urate retention in the latter animals. In retrospect such findings are not surprising in light of the fact that many drugs have the ability to inhibit both secretion and reabsorption. All other things being equal, it is obvious that inhibition of the more prominent system will have the dominant effect on excretion. The rabbit is not easily placed in either of the foregoing categories. Depending on experimental conditions (and probably individual variation) either net secretion or reabsorption is seen. In some instances when the dominant transport system is impeded by drugs or other measures net transport in the opposite direction is observed. This is presumably a consequence of bidirectional urate transport. Considerable effort has been expanded in determining the intrarenal sites of urate transport and thus the sites of drug action. Much of the work has been done with the stop-flow technique. In the mongrel dog, cat, rabbit and Cebus monkey normal net reabsorption has been assigned to the proximal tubule. In the dog and Cebus the major site of urate secretion is also the proximal tubule. In animals that normally show net secretion, the results of stop--flow experiments indicate that secretion occurs in the proximal tubules of Dalmatian Coach Hounds, rabbits, guinea pigs and goats. More precise localizations have been made with mieropuncture and related technique in a few instances. In Cebus both the secretory and reabsorptive fluxes seem to be largely coextensive in the proximal convoluted tubule. In rabbits net reabsorption predominates in the proximal convolution (although bidirectional transport probably occurs there) and net secretion in the latter part of the proximal tubule (the straight part of pars recta). A similar situation obtains in
the Dalmatian Coach Hound. In rats there is obviously bidirectional transport in the proximal convolutions but the direction o f net transport in this segment and the importance o f later segments is still debated. I favor the view that the rat resembles Cebus in this context. In snakes net urate secretion occurs throughout the proximal tubule. It may be important that in the two mammals which secrete urate and which have been studied with microtechniques, that net urate secretion occurs in the pars recta. This may explain why inhibitors of secretion uncover only modest net reabsorption, i.e. the major reabsorptive site is proximal to the major secretory site. In other animals in which secretion and reabsorption are more nearly coextensive, inhibitors of secretion may have much more profound effects, e.g. man, chimpanzee. There is evidence in snakes, dogs, monkeys and chimpanzees that the secretory mechanism for urate is distinct from that for other organic anions such as p-aminohippurate, although both processes occur in the same nephron segments. However, the specificity of the two secretory mechanisms is not great and in mammals at least, inhibitors of one system often inhibit the other. In the following paragraphs I will summarize briefly the drug effects in the various non-human species for which there is substantial information. Because of insufficient information it will not be possible to take into account the effects of differing plasma concentrations of urate in the various animals and various experimental settings. It will be remembered that the tissues of most mammals (except man and great apes) contain the enzyme, uricase, which keeps the level of urate in the circulation very low. In many of the experiments in the literature urate has been infused to elevate urate levels in part for analytical convenience.
Chimpanzee The general pattern of urate excretion has already been described. Probenecid, a probenecid derivative (2-nitroprobenecid), sulfinpyrazone, zoxazolamine, salicylate, carinamide, iodopyracet, chlorothiazide (acutely), halofenate and mersalyl are all uricosuric in this animal. All of the foregoing substances are also uricosuric in man. In general, the intensity of uricosuria with any given dose seems greater in the chimpanzee than in man. This difference has been specifically confirmed with salicylate, probeneeid and mersalyl. Pyrazinoate depresses urate excretion and prevents the uricosuric response to some but not all o f the foregoing drugs. Pyrazinoate reduces the uricosuric response to most o f the remaining drugs. Pyrazinoate in very large doses is uricosurie. Cebus monkeys The general pattern of urate excretion is similar to that of the chimpanzee and man. Probenecid,
Comparative pharmacology of uricosuric drugs 2-substituted probenecid derivatives, sulfmpyrazone, benziodarone, phenylbutazone, salicylate, iodopyracet, mersalyl, and chlorothiazide (acutely) are uricosuric; zoxazolamine at the doses tested was not. In general the uricosuric responses are inferior to those observed in man. Pyrazinoate depresses urate excretion and has been shown to depress the uricosurie responses to some of the foregoing drugs. Nicotinic acid, m-hydroxybenzoic acid and 2,4dinitrophenol also depress urate excretion. Pyrazinoate in very large doses is uricosurie. As noted previously this is the only primate for which there are data from micropuncture studies.
Dogs In non-Dalmatian dogs urate reabsorption predominates over secretion and both processes occur in the proximal tubule. In general drug effects are very difficult to observe. One gains the impression that drug effects are somewhat more easily demonstrable when studies are conducted at endogenous levels of urate. Probenecid and probenecid derivatives exert slight uricosuric actions, as does ouabain. Pyrazinoate in large doses is uricosuric but at lower doses has no effect on overall urate excretion. However, very small amounts of pyrazinoate and other substances definitely suppress the secretory process when the latter is specifically studied. It may well be that both secretion and reabsorption are inhibited to approximately equal extents by drugs and that this accounts for the lack of easily appreciated changes in net secretion. In the Dalmatian Coach Hound (net secretion of urate) substances which are ordinarily uricosuric in man tend to decrease urate excretion as does pyrazinoamide. In some instances inhibitors of secretion uncover net reabsorption. Rabbit These animals may demonstrate either net secretion or net re,absorption of urate. Both processes occur in the proximal tubule, although secretion predominates in the pars recta. In some studies net secretion has been correlated with elevated levels of plasma urate or with intensity of osmotic diuresis. When secretion occurs it is depressed by probenecid. The following have been shown to depress re,absorption in stop--flow experiments: ehlorothiazide, lactate, creatinine and pyrazinoate. Guinea pig The majority of specimens demonstrate net secretion o f urate which occurs in the proximal tubule. Net secretion is inhibited by probenecid and converted to net reabsorption (also a proximal tubular process). Pyrazinoate causes a modest inhibition of secretion. Chlorothiazide and ouabaln had minimal activities. Rat Clearance studies demonstrate overall net rcabsorption of urate. It is not yet entirely clear which
is the net direction of urate transport in the proximal convolutions although the weight of the evidence favours reabsorption. There is, however, general agreement that bidirectional transport occurs in the proximal tubule. Probenecid has a substantial uricosuric effect when plasma urate is low and a modest effect when plasma urate is elevated. On the other hand pyrazinamide (andp-aminohippurate) depressed urate excretion when plasma level of urate was high, but the effect at lower levels of urate was modest. In microinjection experiments the reabsorptive flux of urate was inhibited by p-aminohippurate, probenecid and pyrazinoate. Definite evidence for the inhibition of the secretory flux by pyrazinoate is also available. Hydrochlorothiazide and sulfinpyrazone have no effect on net excretion in acute experiments, although an indirect action of thiazides has been demonstrated, i.e. urate excretion was depressed secondary to volume depletion.
Chicken There is extensive net secretion of urate in this species. Probenecid, sulfinpyrazone, zoxazolamine, phenylbutazone, p-aminohippurate, chlorothiazide, salicylate and 2,4-dinitrophenol have been shown to depress urate secretion. Pyrazinamide was ineffective in two studies, but it is not known whether or not it was converted to the active metabolite, pyrazinoate. It appeared for a time that all drugs which acted on urate excretion in the chicken depressed secretion, i.e. there was no evidence for reabsorption. However, Quebbemann and his colleagues have recently demonstrated that ethacrynic acid and furosemide cause considerable enlaancement of urate excretion. They suggest that the latter drugs inhibit a reabsorptive process. Snakes The snake (Natrix and Thamnophis spp.) demonstrates net secretion of urate which occurs in proximal tubules. The evidence is clear that the active transport step in secretion occurs at the basilar membrane of the tubular cell. There is also a re,absorptive flux of urate in proximal tubules; the evidence currently available suggests that this flux is passive. Should the latter be true it would represent a marked difference from certain mammals. The evidence that urate and p-aminohippurate are secreted by separate mechanisms is convincing. Both secretory mechanisms are inhibited by probenecid. The Hterature Two recent, extensive reviews are available (Mudge et al., 1973; Gutman & Yi, 1972). In addition, much of the more recent literature has been covered by Lassiter (1975) and also appears in a symposium issue of Nephron (Rieselbach & Steele, 1975). Danzler's elegant work on the snake kidney can be traced through a recent paper
4
I . M . WEINER
(Dantzler, 1974). Fanelli & Beyer have provided a comprehensive review of urate disposition in nonhuman primates (Fanelli & Beyer, 1974). Unfortunately, a substantial amount of material included in this paper has been gathered from recent abstracts and personal communications concerning papers in press.
REFERENCES
Mtrr~E G. H.,BErtNDTW. O. &VALTENH. (1973) Tubular transport of urea, glucose, phosphate, uric acid, sulfate and thiosulfate. In Handbook of Physiology, Section 8, Renal Physiology (Edited by ORLOFr J. & B~RLINER
R. W. pp. 587-652. American Physiological Society, Washington, D.C. GUTMANA. B. & Yt~ T. F. (1972) Renal mechanisms for regulation of uric acid secretion, with special reference to normal and gouty men. Sere. Arthritis Rheum. 2, I--46. LASSITER W. E. (1975) Kidney. Ann. Rev. Physiol. 37, 371-393. RIESELBACHR. E. & STEELET. n . (Editors) (1975) Symposium on the influence of the kidney upon urate homeostasis in man. Nephron 14, 1-116. DANZLERW. H. (1974) PAH transport by snake proximal renal tubules: differences from urate transport. Am. J. Physiol. 226, 634-641. FANELLIG. M. Jr., & BEYERK. H. Jr. (1974) Uric acid in nonhuman primates with special reference to its renal transport. Ann. Rev. Pharmacol. 14, 355-364.
