Effects of furosemide on glomerular filtration rate and clearance of practolol, digoxin, cephaloridine, and gentamicin Furosemide was shown to decrease inulin clearance in 20 of 27 normal subjects. The depression in inulin clearance occurred in both water-loaded and non-water-loaded subjects. The renal clearance of practolol, but not digoxin, was reduced when furosemide was given. The average total plasma clearances of gentamicin and of cephaloridine over a 6-hr period were decreased after furosemide. The reduced clearances of the antibiotics were associated with higher plasma levels, the increase in antibiotic concentration being as much as 100% at 1 hr after an intravenous bolus injection.
W. J. Tilstone, Ph.D., P. F. Semple,· D. H. Lawson, M.D., and
J. A. Boyle, M.D.·· Glasgow, United Kingdom Forensic Science Unit, Department of Pharmaceutical Chemistry, University of Strathclyde, and Medical Division, Royal Infirmary
Furosemide is a potent diuretic which acts by inhibition of active chloride transport in the thick ascending limb of the loop of Henle. 6 Furosemide has been reported to induce an increase 14, 15, 19, 22 and a decrease 12 in glomerular filtration rate. The drug is widely used, and it is therefore likely that it may alter the clearance of other drugs if these are eliminated largely by the kidney. We report the results of a series of investigations into such drug interactions. The drugs Supported by a grant from the Scottish Home and Health Department. Presented in part at the Fifth Annual Meeting of the American College of Clinical Pharmacology, Philadelphia, April. 1976. Received for publication Jan. 22, 1977. Accepted for publication May 13, 1977. Reprint requests to: W. J. Tilstone, Forensic Science Unit, University of Strathclyde, Royal College, George Street, Glasgow, GI IXW, United Kingdom. -Present address: M.R.C. Blood Pressure Unit, Western Infirmary, Glasgow. *-Present address: Pfizer Europe, Brussels.
were practolol, digoxin, gentamicin, and cephaloridine. Of these, practolol is rarely given with furosemide, but since it is eliminated almost entirely by glomerular filtration it is a good marker for the postulated interaction. The other three drugs are eliminated by filtration as well as by other mechanisms. They are also much more likely to be given with furosemide and thus interaction may be of clinical significance. Despite its low therapeutic index, 1 no such interaction has been reported with digoxin. On the other hand furosemide interactions have been reported which led to deafness with gentamicin 13 and nephrotoxicity with cephaloridine. 8 Methods
Glomerular filtration rate and clearance measurements. The experiments with practolol and digoxin were designed to study the effect of furosemide on the renal clearance of these drugs 389
390
Tilstone et al.
Clinical Pharmacology and Therapeutics
Table I. Proportion of normal subjects showing a change in glomerular filtration rate when given furosemide Subjects Water loaded* Normal hydrationt
I Ris~ i~ GFRl
Fall in GFR
3/18
14/18
1/9
6/9
'Saline infusion. 300 ml/hr GFR measured as mean of two con· secutive standard clearances before and after furosemide (20 mg). tGFR measured as average clearance of intravenous bolus of inulin given alone or together with furosemide.
and relate any changes to simultaneously determined values of glomerular filtration rate (GFR) measured as the renal clearance of inulin. The inulin was introduced as an intravenous bolus loading dose of 0.26 ml/kg body weight of a 10% w/v solution of inulin in saline followed by an infusion of 300 ml/hr of a 0.29% w/v solution in saline. This protocol produced constant plasma levels of inulin and the subjects were considered to be moderately hydrated. Water was taken in volumes equal to those of urine voided. Urine collections were made for 5 consecutive periods of 30 or 60 minutes from the time of the intravenous bolus of inulin. Clearances were not computed in the first of these periods since arteriovenous equilibrium would not have been reached. Renal clearances were measured in the second, third, fourth, and fifth periods with the use of the standard formula relating renal clearance to urine flow, concentration of solute in plasma, and concentration of solute in urine. GFR was measured as renal clearance of inulin with the use of the plateau concentration in plasma, and drug clearances (practolol and digoxin) were measured by means of the logarithmic mean of the plasma concentrations at the start and end of the time period. 17 The clearance values before and after furosemide are the means of the second and third and fourth and fifth periods, respectively. It was appreciated that any changes in these clearance values would be of significance only if they resulted in a significant change in the average total plasma clearance of inulin or drug during one dose interval, a period of time appreciably longer than the individual periods in the renal clearance studies. For this reason, a different methodology was used in the anti-
biotic studies. Inulin, gentamicin, and cephaloridine were all given in the form of an intravenous bolus. For each, the zero to infinity area under the plasma concentration-time curve was measured by computer fitting of the data. 11 Clearance, which is average GFR in the case of inulin, was measured as the ratio of the dose given to the zero to infinity area. In some experiments, renal clearances over a shorter period of time were made by the method described above to measure renal clearance of digoxin and practolol. In addition to showing the effects of furosemide on average total plasma clearance of drug in contrast to possible transient changes in renal clearance, this protocol allowed randomization of the order of the control and experimental periods and also allowed measurements to be made in the absence of the mild water loading associated with the infusion technique. Chemical assays. Inulin was measured by the colorimetric method of Var/ey21 following acid hydrolysis. 21 Blank plasma samples were assayed simultaneously. The coefficient of variation was 4.1 %. Practolol was measured by the fluorimetric procedure of Bodem and Chidsey. 3 Blank plasma samples were assayed simultaneously. The coefficient of variation was 5.3%. Digoxin was measured by radioimmunoassay. 18 Urine digoxin was assayed by diluting urine at least 1 : 5 in digoxin-free plasma and assaying as plasma. The coefficient of variation was 6.1 %. Gentamicin was assayed by the acetyl transferase method of BroughaU and Reeves. 4 The coefficient of variation was 5.2%. The urine samples were assayed by diluting at least 1: 4 with gentamicin-free plasma. Cephaloridine was measured by liquid chromatography. * The coeficient of variation was 6.7%. Subjects and protocols. The studies were performed in young, healthy, adult men aged 20 to 26 yr. In the practolol and digoxin studies, the appropriate drug was taken orally (100 mg and 0.5 mg, respectively) 30 min before clearance measurements began. The subjects urinated and inulin administration proceeded. Furosemide was given as a 20-mg intravenous bolus at the end of the third clearance period. Ten subjects participated in the practolol study ·Chamberlain. J.: Personal communication.
Effects of furosemide on drug clearance
Volume 22 Number 4
391
Table II. Effect of furosemide on glomerular filtration rate Glomerular filtration rate (ml/min; mean ± SE) Subjects
Control
Furosemide (20 mg intravenously)
Water loaded* Normal hydration
126 ± 8.3 (18)
88 ± 8.0 (18) 78 ± 5.0 (9)
129 ± 5.5 (9)
p
W. J. Tilstone, Ph.D., P. F. Semple,· D. H. Lawson, M.D., and
J. A. Boyle, M.D.·· Glasgow, United Kingdom Forensic Science Unit, Department of Pharmaceutical Chemistry, University of Strathclyde, and Medical Division, Royal Infirmary
Furosemide is a potent diuretic which acts by inhibition of active chloride transport in the thick ascending limb of the loop of Henle. 6 Furosemide has been reported to induce an increase 14, 15, 19, 22 and a decrease 12 in glomerular filtration rate. The drug is widely used, and it is therefore likely that it may alter the clearance of other drugs if these are eliminated largely by the kidney. We report the results of a series of investigations into such drug interactions. The drugs Supported by a grant from the Scottish Home and Health Department. Presented in part at the Fifth Annual Meeting of the American College of Clinical Pharmacology, Philadelphia, April. 1976. Received for publication Jan. 22, 1977. Accepted for publication May 13, 1977. Reprint requests to: W. J. Tilstone, Forensic Science Unit, University of Strathclyde, Royal College, George Street, Glasgow, GI IXW, United Kingdom. -Present address: M.R.C. Blood Pressure Unit, Western Infirmary, Glasgow. *-Present address: Pfizer Europe, Brussels.
were practolol, digoxin, gentamicin, and cephaloridine. Of these, practolol is rarely given with furosemide, but since it is eliminated almost entirely by glomerular filtration it is a good marker for the postulated interaction. The other three drugs are eliminated by filtration as well as by other mechanisms. They are also much more likely to be given with furosemide and thus interaction may be of clinical significance. Despite its low therapeutic index, 1 no such interaction has been reported with digoxin. On the other hand furosemide interactions have been reported which led to deafness with gentamicin 13 and nephrotoxicity with cephaloridine. 8 Methods
Glomerular filtration rate and clearance measurements. The experiments with practolol and digoxin were designed to study the effect of furosemide on the renal clearance of these drugs 389
390
Tilstone et al.
Clinical Pharmacology and Therapeutics
Table I. Proportion of normal subjects showing a change in glomerular filtration rate when given furosemide Subjects Water loaded* Normal hydrationt
I Ris~ i~ GFRl
Fall in GFR
3/18
14/18
1/9
6/9
'Saline infusion. 300 ml/hr GFR measured as mean of two con· secutive standard clearances before and after furosemide (20 mg). tGFR measured as average clearance of intravenous bolus of inulin given alone or together with furosemide.
and relate any changes to simultaneously determined values of glomerular filtration rate (GFR) measured as the renal clearance of inulin. The inulin was introduced as an intravenous bolus loading dose of 0.26 ml/kg body weight of a 10% w/v solution of inulin in saline followed by an infusion of 300 ml/hr of a 0.29% w/v solution in saline. This protocol produced constant plasma levels of inulin and the subjects were considered to be moderately hydrated. Water was taken in volumes equal to those of urine voided. Urine collections were made for 5 consecutive periods of 30 or 60 minutes from the time of the intravenous bolus of inulin. Clearances were not computed in the first of these periods since arteriovenous equilibrium would not have been reached. Renal clearances were measured in the second, third, fourth, and fifth periods with the use of the standard formula relating renal clearance to urine flow, concentration of solute in plasma, and concentration of solute in urine. GFR was measured as renal clearance of inulin with the use of the plateau concentration in plasma, and drug clearances (practolol and digoxin) were measured by means of the logarithmic mean of the plasma concentrations at the start and end of the time period. 17 The clearance values before and after furosemide are the means of the second and third and fourth and fifth periods, respectively. It was appreciated that any changes in these clearance values would be of significance only if they resulted in a significant change in the average total plasma clearance of inulin or drug during one dose interval, a period of time appreciably longer than the individual periods in the renal clearance studies. For this reason, a different methodology was used in the anti-
biotic studies. Inulin, gentamicin, and cephaloridine were all given in the form of an intravenous bolus. For each, the zero to infinity area under the plasma concentration-time curve was measured by computer fitting of the data. 11 Clearance, which is average GFR in the case of inulin, was measured as the ratio of the dose given to the zero to infinity area. In some experiments, renal clearances over a shorter period of time were made by the method described above to measure renal clearance of digoxin and practolol. In addition to showing the effects of furosemide on average total plasma clearance of drug in contrast to possible transient changes in renal clearance, this protocol allowed randomization of the order of the control and experimental periods and also allowed measurements to be made in the absence of the mild water loading associated with the infusion technique. Chemical assays. Inulin was measured by the colorimetric method of Var/ey21 following acid hydrolysis. 21 Blank plasma samples were assayed simultaneously. The coefficient of variation was 4.1 %. Practolol was measured by the fluorimetric procedure of Bodem and Chidsey. 3 Blank plasma samples were assayed simultaneously. The coefficient of variation was 5.3%. Digoxin was measured by radioimmunoassay. 18 Urine digoxin was assayed by diluting urine at least 1 : 5 in digoxin-free plasma and assaying as plasma. The coefficient of variation was 6.1 %. Gentamicin was assayed by the acetyl transferase method of BroughaU and Reeves. 4 The coefficient of variation was 5.2%. The urine samples were assayed by diluting at least 1: 4 with gentamicin-free plasma. Cephaloridine was measured by liquid chromatography. * The coeficient of variation was 6.7%. Subjects and protocols. The studies were performed in young, healthy, adult men aged 20 to 26 yr. In the practolol and digoxin studies, the appropriate drug was taken orally (100 mg and 0.5 mg, respectively) 30 min before clearance measurements began. The subjects urinated and inulin administration proceeded. Furosemide was given as a 20-mg intravenous bolus at the end of the third clearance period. Ten subjects participated in the practolol study ·Chamberlain. J.: Personal communication.
Effects of furosemide on drug clearance
Volume 22 Number 4
391
Table II. Effect of furosemide on glomerular filtration rate Glomerular filtration rate (ml/min; mean ± SE) Subjects
Control
Furosemide (20 mg intravenously)
Water loaded* Normal hydration
126 ± 8.3 (18)
88 ± 8.0 (18) 78 ± 5.0 (9)
129 ± 5.5 (9)
p
