Binding and disposition of sulfisoxazole in alcoholic cirrhosis

The disposition of sulfisoxazole was studied in six male patients hospitalized with biopsy-proven Laennec's alcoholic cirrhosis and six normal, healthy volunteers. Four of the patients were restudied at a time their liver disease had improved clinically. On the average, compared to the normal group, the metabolism of sulfisoxazole (clearance values with respect to unbound concentration values) appears to be unaltered for the cirrhotic patients. For patients with alcoholic cirrhosis having normal renal function for age and weight, the renal elimination of sulfisoxazole was normal For those subjects with decreased renal function, the renal clearance of sulfisoxazole appeared to be disproportionately decreased, as evidenced by a lower-than-normal sulfisoxazole renal clearance-to-creatinine clearance values. The apparent steady-state volume of distribution of unbound sulfisoxazole was not altered in cirrhotic patients when compared to normal subjects, while the apparent volume of distribution of total drug increased by more than what could be expected from protein binding changes alone. The elimination rate constant did not differ from values found in normals. These data suggest that the total binding capacity of sulfisoxazole in cirrhotic patients is not different from that of normal subjects.Supported in part by Grants GM 25807, GM 28423, HL-11046 and AM-06415 from National Institutes of Health.     

Pharmacokinetics of sulfisoxazole in rabbits with experimental renal failure after single and multiple dosing

In rabbits injected intravenously with 0.75 mg/kg uranyl nitrate to precipitate acute renal failure, the renal elimination of sulfisoxazole was essentially non-existent 3 days after the injection. In addition a significant (40%) reduction in the metabolic elimination (unbound clearance) was observed in the renal failure animals. Whether the decrease in metabolic clearance is due to a decrease in renal or non-renal metabolism is not clear from the available data. The protein binding dramatically decreased in renal failure animals, with the lowest binding occurring during the multiple dosing therapy. The half-life is greater (2–3 times) and the apparent volume of distribution (unbound) is significantly decreased due to decreased binding in plasma and tissues.     

Pharmacokinetics of erythromycin in patients with severe cirrhosis. Respective influence of decreased serum binding and impaired liver metabolic capacity.

Pharmacokinetic parameters were studied after i.v. infusion of erythromycin (500 mg) in five patients with alcoholic cirrhosis and six normal subjects. Serum AAG levels were 4.7 +/- 2.4 mumol l-1 in cirrhotics and 10.3 +/- 2.1 +/- mumol l-1 in normals. The unbound fraction (fu) of erythromycin was significantly higher in cirrhotic patients (58.3 +/- 17.7%) than in normal subjects (30.5 +/- 2.8%, P less than 0.01), and a negative correlation was found between fu values and serum AAG (r = -0.867, P less than 0.01). Due to increase in fu, volume of distribution (Vss) was significantly augmented in cirrhotics (85.5 +/- 23.8 l vs 57.6 +/- 14.8 l, P less than 0.05). Serum clearance of unbound erythromycin (CLu) was significantly reduced in cirrhotic patients (42.2 +/- 10.1 l h-1 vs 113.2 +/- 44.2 l h-1 in normal subjects, P less than 0.01). This led to marked elevation of serum concentrations of unbound drug and was entirely explained by the decrease of non renal (i.e. hepatic intrinsic) clearance (31.6 +/- 7.5 l h-1 in cirrhotics, 98.6 +/- 41.5 l h-1 in normals, P less than 0.02); renal clearance remained unchanged. It is concluded that in cirrhotic patients, low serum AAG levels and reduced liver metabolic capacity may lead to marked changes in pharmacokinetics of erythromycin, and that similar results might be expected for drugs which exhibit the same serum binding and pharmacokinetic behaviour as erythromycin.     

Comparison of the disposition of total and unbound sulfisoxazole after single and multiple dosing

Plasma concentrations of total and unbound sulfisoxazole were followed after single intravenous and oral doses of 1 g sulfisoxazole and during a 500-mg, four-time-a-day dosing regimen in six healthy males, using a specific high pressure liquid Chromatographic assay method. Saturable plasma protein binding was observed at total concentrations above 80–100 mg/liter. The clearance of sulfisoxazole was 18.7±3.9ml/min for total drug and 232±64ml/min for unbound drug. Renal elimination, on the average, accounted for 49% of the clearance of sulfisoxazole. The apparent volume of distribution for total drug was 10.9±2.0 liters and 136±36 liters for unbound drug, indicating that sulfisoxazole is primarily distributed extracellularly. Accumulation of N4-acetyl-sulfisoxazole during multiple dosing did not affect the disposition of sulfisoxazole. Adjusting for variable renal clearances between oral and intravenous administration and using the unbound plasma concentrations, the bioavailability for an oral dose of sulfisoxazole was found to be 0.95±0.04.Supported in part by grant GM 25807 from the National Institutes of Health.     

Clofibrate disposition in renal failure and acute and chronic liver disease

Summary The disposition of clofibrate over 96 hours was observed following single oral dose in six patients with acute viral hepatitis, six patients with liver cirrhosis, seven patients with renal insufficiency, and six control subjects. No parameter of the disposition of CPIB (active form of clofibrate) was significantly altered in acute hepatitis. In liver cirrhosis, the mean plasma half-life was unchanged compared to controls (20.9 vs. 17.5 h), but plasma clearance of the non-protein bound drug was reduced (115 vs. 243 ml×min^–1), plasma protein binding was reduced (92.8 vs. 97.2 percent), and the apparent volume of distribution was increased (0.20 vs. 0.141×kg^–1). In renal insufficiency plasma half-life was prolonged 2 to 6-fold, depending on the degree of renal impairment. Total plasma clearance (3.4 vs. 7.1 ml×min^–1) and plasma clearance of the unbound drug (81 vs. 243 ml×min^–1 were reduced in patients with renal failure, the clearance of the unbound drug being inversely correlated with the serum creatinine concentration. Renal failure was also associated with decreased protein binding and an increased volume of distribution of CPIB, and with reduced urinary excretion of CPIB and its glucuronide metabolite. The dose of clofibrate should be halved in patients with cirrhosis. In renal insufficiency, the dose should be adjusted according to the individual serum creatinine level: only 10 to 15% of the usual weekly dose should be given in complete renal failure.     

Disopyramide pharmacokinetics and bioavailability following the simultaneous administration of disopyramide and 14C-disopyramide

The pharmacokinetics and bioavailability of total (bound plus unbound) and unbound disopyramide were compared following the simultaneous administration of an oral dose of disopyramide and an intravenous dose of 14C-disopyramide in five normal volunteers and in 11 patients with congestive heart failure. The binding of disopyramide varied between 60 and 92% in patients and between 81 and 88% in normal subjects at postequilibrium drug concentrations of 10(-7) M. The binding of disopyramide to serum protein was concentration-dependent in all study subjects at serum concentrations achieved following drug administration. The association constant for the first binding site in serum from normal subjects and patients averaged 8.7 X 10(5) M-1 and 4.4 X 10(5) M-1, respectively (p less than 0.05). The unbound clearance of disopyramide averaged 277 ml/min and 209 ml/min in normal subjects and in patients (p less than 0.05). When normalized for body weight, the unbound clearance between patients and normal subjects was not significantly different. The elimination half-life of unbound concentrations in normal subjects and in patients averaged 4.9 and 6.1 h, respectively (p less than 0.05). The clearance and elimination half-life of total disopyramide was the same in both groups. Although the bioavailability of disopyramide averaged 0.85 in both groups, it was more variable in patients owing to the variability in the fraction of the dose absorbed. The unbound renal clearance and volume of distribution at steady state of disopyramide was related to cardiac index. The ratio of elimination half-lives of total and unbound disopyramide was related to the extent of serum protein binding.     

Antipyrine clearance and metabolite formation in patients with alcoholic cirrhosis.

The effect of liver cirrhosis on plasma clearance and metabolite profile of i.v. administered antipyrine was studied in 23 patients with alcoholic liver cirrhosis (age 37-70 years) and 17 healthy subjects (age 28-55 years). Liver volume was also measured and was found to be larger in patients than in controls, mean values being 1.86 and 1.36 l respectively. The elimination half-life of antipyrine in patients with alcoholic liver cirrhosis was significantly longer than in the healthy subjects (P less than 0.001). Mean values were 39.9 and 10.1 h respectively. Alcoholic liver cirrhosis had no effect on the apparent volume of distribution of antipyrine, but antipyrine plasma clearance was substantially reduced in the patients. Mean clearance values (ranges) were 13.5 (9.3-22.8) ml/min in the patients and 49.3 (31.1-103) ml/min in healthy subjects. Normalization of antipyrine plasma clearance for liver volume resulted in an only slightly increased distinction between patients and healthy subjects, mean values (ranges) being 7.8 (3.3-13.0) ml min(-1) 1(-1) and 36.1 (21.9-35.9) ml min(-1) 1(-1) respectively. The cumulative renal excretion of 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) was significantly lower in patients with alcoholic liver cirrhosis than in healthy subjects, as was the total recovery of antipyrine and major metabolites from urine. Mean values were 15.0, 8.4 and 41.2% of dose in the patients respectively and 24.3, 25.8 and 68.9% of dose in the control subjects. Excreted amounts of total and unconjugated 3-hydroxymethylantipyrine (HMA) and of unchanged antipyrine were the same in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Duloxetine pharmacokinetics in cirrhotics compared with healthy subjects

OBJECTIVE: To compare the pharmacokinetics of single-dose duloxetine in cirrhotic and healthy subjects. METHODS: An open-label inpatient study compared duloxetine pharmacokinetics in six subjects with moderate liver cirrhosis (Child-Pugh class B) to those in six healthy subjects. Subjects received a single 20 mg capsule of duloxetine following overnight fasting. Blood samples were collected up to 120 h post dose for determination of plasma concentrations of duloxetine and its major metabolites using a validated LC/MS/MS method. Plasma concentration-time data for duloxetine and its major metabolites were analyzed by noncompartmental methods. Specific pharmacokinetic parameters were assessed statistically using a mixed-effects model. RESULTS: Duloxetine apparent clearance was significantly lower (24 vs 160 l/h, p < 0.05) and AUC values were substantially higher (775 vs 268 ng x (h/ml) in cirrhotic compared to healthy subjects. The half-life of duloxetine was about three times longer (47.8 vs 13.5 h) in cirrhotic than in healthy subjects (p < 0.05). In contrast, there was no significant difference in Cmax or apparent volume of distribution between the two groups. The metabolites exhibited lower levels and longer half-lives in cirrhotic subjects compared to healthy subjects. The lower clearance and slower elimination of duloxetine in cirrhotic individuals is likely attributable to impaired duloxetine metabolism. CONCLUSIONS: The rate of duloxetine elimination is reduced for cirrhotic subjects, making dosage adjustments appropriate. Based on simulations, the duloxetine dose for at least an initial treatment period may need to be reduced and/or less frequently administered for patients with moderate cirrhosis.     

Effect of serum protein binding on sulfisoxazole distribution, metabolism, and excretion in rats.

This investigation determined the effect of serum protein binding on the kinetics of sulfisoxazole distribution, metabolism, and excretion. Adult rats, whose serum free fraction of sulfisoxazole (at a total concentration of 81 +/- 6 micrograms/ml) was 0.05-0.24, received a rapid intravenous injection of 20 mg/kg. Sulfisoxazole concentrations in plasma declined biexponentially with time. There were pronounced and reproducible interindividual differences in the total, metabolic, and renal sulfisoxazole clearances, each positively correlated with the serum free fraction of sulfisoxazole. The renal sulfisoxazole clearance had a component unaffected by serum protein binding. The apparent central compartment volume increased with an increasing serum free sulfisoxazole fraction, but the latter had not apparent effect on the first exponential term of the biexponential equation describing sulfisoxazole elimination kinetics in rats. Serum protein binding was a major determinant of intersubject differences in sulfisoxazole excretion and biotransformation kinetics.     

Effect of 4-N-acetyl-sulfisoxazole on the disposition of sulfisoxazole in the rat

The plasma protein binding of sulfisoxazole in the rat was found to be decreased in the presence of the major metabolite of sulfisoxazole, 4-N-acetyl-sulfisoxazole. This resulted in an increase in the total clearance and apparent volume of distribution of sulfisoxazole. However, both total and renal clearance of unbound drug from the body were decreased, indicating that the intrinsic ability to metabolize and renally eliminate sulfisoxazole is decreased by the presence of the major metabolite, 4-N-acetyl-sulfisoxazole.     

Disopyramide pharmacokinetics and bioavailability following the simultaneous administration of disopyramide and14C-disopyramide

The pharmacokinetics and bioavailability of total (bound plus unbound) and unbound disopyramide were compared following the simultaneous administration of an oral dose of disopyramide and an intravenous dose of¹⁴C-disopyramide in five normal volunteers and in 11 patients with congestive heart failure. The binding of disopyramide varied between 60 and 92% in patients and between 81 and 88% in normal subjects at postequilibrium drug concentrations of 10^–7M. The binding of disopyramide to serum protein was concentration-dependent in all study subjects at serum concentrations achieved following drug administration. The association constant for the first binding site in serum from normal subjects and patients averaged 8.7X10⁵ M^–1 and 4.4X10 ⁵ M^–1, respectively (p < 0.05). The unbound clearance of disopyramide averaged 277ml/min and 209 ml/min in normal subjects and in patients (p < 0.05). When normalized for body weight, the unbound clearance between patients and normal subjects was not significantly different. The elimination half-life of unbound concentrations in normal subjects and in patients averaged 4.9 and 6.1 h, respectively (p < 0.05). The clearance and elimination half-life of total disopyramide was the same in both groups. Although the bioavailability of disopyramide averaged 0.85 in both groups, it was more variable in patients owing to the variability in the fraction of the dose absorbed. The unbound renal clearance and volume of distribution at steady state of disopyramide was related to cardiac index. The ratio of elimination half-lives of total and unbound disopyramide was related to the extent of serum protein binding.This work was supported by Grant GM-28424 from the National Institute of General Medical Sciences, National Institutes of Health.     

Single-dose pharmacokinetics of pravastatin and metabolites in patients with renal impairment.

The disposition of a single 20-mg oral dose of pravastatin was assessed in subjects with various degrees of renal function. Sixteen subjects (13 males, 3 females) with creatinine clearance values ranging from 15 to 112 mL/min/1.73 m2 completed the study. Area under the serum concentration-time curve, maximum serum concentration, time to maximum serum concentration, terminal serum elimination half-life, apparent clearance, and apparent volume of distribution for pravastatin were not affected by renal impairment, whereas the renal clearance of pravastatin decreased as creatinine clearance decreased (r2 = 0.697, P less than .001). The area under the serum concentration-time curve and time to maximum serum concentration of SQ 31,945 (a hepatic metabolite) increased in patients with renal impairment, whereas the terminal elimination rate constant and renal clearance of SQ 31,945 significantly decreased as a function of creatinine clearance. The renal clearance of another metabolite (SQ 31,906) also significantly declined with decreasing renal function. This single-dose study demonstrates that pravastatin pharmacokinetics were not affected in patients with renal impairment, probably because of its dual route of elimination.     

Does alpha1-acid glycoprotein reduce the unbound metabolic clearance of disopyramide in patients with renal impairment?

Summary The pharmacokinetics of disopyramide was studied in 15 patients with renal dysfunction (4 with pyelonephritis, 7 with glomerular nephritis and 4 with interstitial nephritis).The elimination rate constant of unbound disopyramide was 0.094 h^–1 and CL_u/f (unbound clearance divided by bioavailability) was 245 ml/min. Both the unbound renal clearance (CL_R) and CL_u/f were highly correlated with the creatinine clearance (CL_CR). The apparent unbound metabolic clearance in the patients was approximately two-fold lower than that previously reported in normal subjects. The estimated unbound metabolic clearance in the renal dysfunction patients showed a significant negative correlation with the ₁-acid glycoprotein (AAG) concentration and only a weak, non-significant correlation with CL_CR.As AAG in the renal dysfunction subjects was increased in comparison with normal values, it is possible that AAG is a factor in the decrease in the apparent unbound metabolic clearance.     

Pharmacokinetics of molsidomine and its active metabolite, linsidomine, in patients with liver cirrhosis.

The pharmacokinetics of molsidomine were investigated in six healthy volunteers and in seven patients with alcoholic cirrhosis. After a 2 mg oral dose, molsidomine elimination half-life was prolonged in cirrhotic patients (13.1 +/- 10.0 h vs 1.2 +/- 0.2 h, P less than 0.01) because of a decrease in its apparent plasma clearance (CL/F) (39.8 +/- 31.9 ml h-1 kg-1 in patients with cirrhosis vs 590 +/- 73 ml h-1 kg-1 in volunteers). The elimination half-life of the active metabolite, linsidomine (SIN-1) was also prolonged in cirrhotic patients (7.5 +/- 5.4 h vs 1.0 +/- 0.19 h, P less than 0.05). The AUC values of both molsidomine and linsidomine were increased in the cirrhotic group, but the increase in the former was considerably greater than in the latter as shown by the significant decrease of the ratio AUClinsidomine/AUCmolsidomine x 100 (4.5 +/- 6.1 in cirrhotic patients vs 23.5 +/- 3.4 in healthy volunteers, P less than 0.001). These results suggest that liver cirrhosis profoundly alters the pharmacokinetics and metabolism of molsidomine.     

Effect of age and liver cirrhosis on the pharmacokinetics of nitrazepam

1 The effect of age and liver cirrhosis on the pharmacokinetics of i.v. administered nitrazepam was studied in nine healthy relatively young subjects (age 22-49 years), eight healthy elderly (age 67-76 years) and 12 patients with alcoholic liver cirrhosis (age 39-66 years).

2 The elimination half-life of nitrazepam in the elderly subjects was longer than in the young ones but the difference did not reach statistical significance. Mean values (ranges) were 38 (26-64) h and 26 (19-31) h respectively.

3 The increase in elimination half-life was primarily due to an increase in volume of distribution, mean values (ranges) being 2.93 (1.96-5.33) l/kg and 1.89 (1.44-2.23) l/kg in the elderly and young groups respectively (P < 0.05).

4 The protein unbound fraction of nitrazepam tended to be higher in the elderly subjects, although the difference between the two age groups was not significant: 13.9 (11.5-15.4)% and 13.0 (11.0-15.9)% in elderly and young respectively.

5 Age had no effect on the clearance of total nitrazepam nor on the clearance of unbound nitrazepam (intrinsic clearance). Mean values (ranges) were 63 (50-87) ml/min and 489 (377-635) ml/min in the young and 64 (47-91) ml/min and 456 (348-652) ml/min in the elderly subjects respectively.

6 There were no significant differences in elimination half life, clearance and volume of distribution between patients with alcoholic liver cirrhosis and the total of healthy subjects of both age groups, mean values (ranges) being 31 (21-55) h, 59 (26-85) ml/min and 2.17 (1.57-3.22) l/kg respectively in patients and 31 (19-64) h, 63 (47-91) ml/min and 2.38 (1.44-5.33) l/kg in healthy subjects.

7 The protein unbound fraction of nitrazepam was substantially higher in the patient group: 18.9 (14.8-30.3)% as compared to 13.8 (11.0-15.9)% in the healthy subjects (P < 0.001).

8 Clearance calculated relative to unbound nitrazepam (intrinsic clearance) was significantly lower in the patient group: 320 (163-482) ml/min as compared to healthy subjects, 472 (348-652) ml/min (P < 0.001).

9 The results of this study indicate that nitrazepam action following single dose administration may be more persistent in elderly than in young people; however, steady state levels of total and unbound nitrazepam during nightly intake of the drug will not be affected by age. On the other hand, steady state levels of unbound nitrazepam in patients with liver cirrhosis will generally be about 35% higher than in healthy subjects.

     

The disposition of intravenous L-tryptophan in healthy subjects and in patients with liver disease.

The disposition of free and of total tryptophan following an intravenous load of 1.5 g of L-tryptophan was evaluated in eight patients with non-cirrhotic liver disease, 40 patients with cirrhosis of the liver (21 Child's A, 15 Child's B, 4 Child's C) and in 14 healthy subjects. Cirrhosis affected disposition of tryptophan by (a) decreasing the clearance of both free and total tryptophan by 64% (P less than 0.001) and 34% (P less than 0.01), respectively, (b) by increasing the apparent volume of distribution of total tryptophan by 42% (P less than 0.01) by expansion of the peripheral compartment, resulting in (c) a threefold increase in the half-life of tryptophan. Apart from a reduction in free tryptophan clearance, these changes in tryptophan disposition were not apparent in patients with non-cirrhotic liver disease. Elevated fasting free tryptophan plasma concentrations are an indicator of impaired tryptophan metabolism in cirrhosis. They result from a decreased hepatic clearance of tryptophan rather than from a reduction in tryptophan protein binding. This study emphasises the markedly differing pharmacokinetic behaviour of tryptophan in cirrhotic patients compared with normal subjects and with patients with non-cirrhotic liver disease.     

Pharmacokinetics of chlormethiazole in healthy volunteers and patients with cirrhosis of the liver

Summary The pharmacokinetics of chlormethiazole after oral and intravenous administration was studied in six healthy volunteers and eight patients with alcoholic cirrhosis of the liver. Plasma concentration-time curve after the intravenous infusion could adequately be described by two- or three-compartment open models both in healthy volunteers and in the patients. Based on the areas under the plasma concentration-time curves, the systemic bioavailability of oral chlormethiazole was about ten times greater in the patients than in healthy controls. The elimination of chlormethiazole was relatively less retarded in the patients, as indicated by a decrease of about 30% in its plasma clearance. In the patients the plasma protein binding of chlormethiazole was decreased, but the volume of distribution and half-life of elimination were unchanged. The increase in bioavailability of chlormethiazole was associated with significant alteration in the serum levels of bilirubin, albumin, alkaline phosphatase, prothrombin-proconvertin activity (P + P) and elimination rate of antipyrine or¹⁴C-aminopyrine. The increased bioavailability of oral chlormethiazole was due to impaired first-pass metabolism in the cirrhotic liver. A considerable reduction in dose seems to be indicated if oral chlormethiazole is used in patients with advanced cirrhosis of the liver. A substantial fraction of dose, averaging 15%, was lost during the intravenous infusion, presumably due to adsorption to the infusion tubing.     

Influence of Serum Protein Binding on the Pharmacokinetics of Quinidine in Normal and Anuric Rats

Abstract The pharmacokinetics of quinidine were investigated in normal and anuric rats after intravenous injection (25 mg per kg b. wt.). In normal rats only 2.6 percent of the injected dose was excreted as unchanged quinidine in the urine. Quinidine concentrations were determined in the blood and in different tissues after injection, and the serum protein binding was measured. Results were applied to a one compartment model. In normal rats a total body clearance of 18.5 ml/min. and a renal clearance of 0.5 ml/min. was found. The residual non-renal clearance (18.0 ml/min.), presumably taking place in the liver, exceeds the estimated liver blood flow (16.8 ml/min.), indicating efficient extraction of quinidine from plasma and blood cells (non-restrictive elimination). The apparent volume of distribution was greatly reduced, biological half-life slightly longer and the body clearance greatly reduced in anuric as compared to normal rats. The fraction of unbound quinidine in serum was 30.6 ± 0.6 (n=23) and 16.7 ± 0.5) (n=23) percent in normal and anuric rats. The reduction in the apparent volume of distribution is mainly explained by increased serum binding. The decline of body clearance of quinidine is most likely caused by a decreased liver blood flow in this complex state of renal insufficiency.     

Single-dose pharmacokinetics of nateglinide in subjects with hepatic cirrhosis

This single-dose, open-label, parallel-group study compared the pharmacokinetics and tolerability of 120 mg doses of nateglinide, a physiologic mealtime glucose regulator for type 2 diabetes, in 8 subjects with cirrhosis and 8 matched healthy subjects. In both groups, plasma concentration peaked in a median of 0.5 hours, and mean terminal elimination half-lives were comparable. Mean +/- SD pharmacokinetic parameters in cirrhotic versus healthy subjects were slightly different (Cmax, 7.7 +/- 4.9 vs. 5.6 +/- 1.3 micrograms/ml; AUC(0-t), 18.5 +/- 7.5 vs. 14.2 +/- 2.1 micrograms.h/ml, respectively). Mean apparent total clearance and mean renal clearance in both groups were comparable. Mean protein-bound fractions were equivalent; binding appeared unaltered by metabolites. One cirrhotic and 2 healthy subjects each reported one adverse event. No statistically significant or clinically relevant alteration in pharmacokinetic parameters of nateglinide resulted from hepatic dysfunction, and it was well tolerated; therefore, adjustment of nateglinide dosage is not required in subjects with mild to moderate cirrhosis.     

Disposition of alfentanil in patients receiving a renal transplant

The disposition of alfentanil has been investigated in 10 anaesthetized patients with chronic renal failure undergoing kidney transplantation and compared with eight age matched anaesthetized patients with normal renal function. Plasma samples were collected to 660 min following intravenous administration of alfentanil 3-5 mg (50 micrograms kg-1). Drug concentrations were measured by RIA; and alfentanil binding to plasma proteins by equilibrium dialysis against 0.1 M phosphate buffer, pH 7.4. Alfentanil binding to plasma proteins was 87.6% (s.d. 2.0) in the patients with chronic renal failure, and 89.7% (1.2) in patients with normal renal function (P = 0.025). There was no correlation between alfentanil binding and plasma albumin, total plasma proteins, plasma urea or plasma creatinine concentrations. In both groups, the drug concentration-time profile decayed in a curvilinear manner; in the chronic renal failure patients, restoration of function did not influence the decay profile. Elimination half life, mean residence time and apparent volume of distribution at steady state were not different in the two groups of patients (mean values: 142.4 and 120.2 min; 128.5 and 136.0 min; and 40.5 and 27.6 L, respectively in chronic renal failure patients and patients with normal renal function). Total drug clearance and Vd area were significantly increased in the chronic renal failure patients: 341.9 vs 211.8 mL min-1; and 69.3 and 35.5 L. There were no differences in intrinsic clearance or apparent volume of distribution at steady state for unbound drug between the two patient groups.