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The antibiotic imipenum (thienamycin-formamidine) is partially hydrolyzed during excretion by a renal brush border dehydropeptidase. The co-administration of imipenum with the renal dehydropeptidase inhibitor cilastatin results in an increase of the urinary recovery of the antibiotic, both in animals and humans. To study the pharmacokinetics of imipenem and cilastatin, subjects with normal renal function and patients with different degrees of renal insufficiency received intravenously 250 mg imipenum alone and 250 mg imipenem with 250 mg cilastatin. The mean plasma half-life of imipenem varied from 52 min in subjects with normal renal function to 173 min in subjects with end-stage renal failure studied while off-dialysis. The plasma half- life of imipenem was not affected by the co-administration of cilastatin. The mean plasma half-life of cilastatin varied from 54 min in normals to 798 min in patients with end-stage renal failure. The co- administration of cilastatin resulted in an increase of the urinary concentration and in the urinary recovery of imipenem, the effect being more pronounced in the subjects with normal or only mildly impaired renal function. The plasma clearance of imipenem was decreased when cilastatin was co-administered, possibly due to inhibition of tubular secretion of imipenem. Elimination studies performed during haemodialysis indicated efficient removal of both imipenem and cilastatin during a 4 h session. In view of the important increase in half-life of cilastatin as a function of increasing renal failure, a dosage reduction is proposed in patients with severe renal failure. It is recommended that the maximum dose of imipenem/cilastatin would be limited to either 1000/1000 mg twice daily or 500/500 mg four times daily in patients with a creatinine clearance of less than 15 ml/min. Also, a supplementary dose of imipenem and cilastatin after dialysis is recommended. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of imipenem and cilastatin after repeated doses have been studied in six patients with severe renal impairment (mean creatinine clearance 10.4 ml/min/1.73 m2). The patients received nine iv injections of imipenem/cilastatin sodium (500/500 mg) at 12-hour intervals. The imipenem plasma concentration-time profile and the pharmacokinetic parameters on day 5 were similar in all respects to those on day 1. Therapeutic plasma levels of imipenem (greater than or equal to 4 mg/l) were maintained for 8-10 h after administration. Most pharmacokinetic parameters of cilastatin were similar on both days. However, the area under the plasma concentration curve (AUC) was significantly increased on day 5, as a result of some accumulation, but the trough levels stabilized after the third injection. Twice daily administration of imipenem/cilastatin 500/500 mg was felt to be a well tolerated and optimal dose regimen in patients with severe renal failure.

A reversed-phase high-performance liquid chromatographic method with ultraviolet detection is described for the quantification of sulindac, sulindac sulfone and sulindac sulfide in plasma and sulindac, trans-sulindac, sulindac sulfone and sulindac sulfide in urine. Plasma samples are de-proteinized with acetonitrile and urine samples are injected directly following enzymatic hydrolysis of glucuronide metabolites. The resulting chromatograms are essentially free from endogenous interference and the limits of detection are 0.1 microgram/ml for plasma and 0.2 microgram/ml for urine for all of the above compounds.

Cilastatin, a dehydropeptidase-I inhibitor, is coadministered with the beta-lactam antibiotic imipenem. The described procedure was developed for quantification of cilastatin in human plasma and urine. The assay involved sample purification on a C18 extraction cartridge, reversed-phase high-performance liquid chromatography with post-column derivatization and fluorescence detection. Standard curves were linear from 0.75 to 75.0 micrograms/ml in plasma and from 2.5 to 200.0 micrograms/ml in urine. Intra-day mean coefficients of variation at concentrations within the standard curve range were 4.2 +/- 2.4% and 3.1 +/- 1.7% in plasma and urine, respectively. The inter-day coefficients of variation for analyses of cilastatin in plasma (1.0 and 50.5 micrograms/ml) were less than 10% after 31 days of analysis while those for urine (5.0 and 74.1 micrograms/ml) were less than 11% after 44 days of analysis. The limits of reliable detection were 0.75 and 2.5 micrograms/ml in plasma and urine, respectively. This procedure met the sensitivity and specificity requirements for the analysis of samples from clinical pharmacokinetic studies.

In normal humans sulindac, a prodrug, undergoes two major biotransformations: irreversible oxidation to the inactive sulfone metabolite and reversible reduction to the pharmacologically active sulfide metabolite. To assess any effect of end-stage renal failure on sulindac biotransformation, six patients were given 200 mg sulindac orally. Plasma was sampled over 24 hours. Protein binding of sulindac and metabolites was determined by equilibrium dialysis. Results were compared with historic controls. AUC(0-12) for sulindac and the sulfone were similar to controls. AUC(0-12) for the sulfide was significantly reduced to 4.85 micrograms X hr/ml from 13.1 micrograms X hr/ml (P less than 0.02). Protein binding of all three compounds was significantly reduced by renal failure. When corrected for protein binding, the AUC(0-12) for sulindac and the sulfone was twice that of controls whereas that of the sulfide was 42 ng X hr/ml compared with 83 ng X hr/ml in normal individuals (P less than 0.001). This suggests that end-stage renal failure impairs the reduction of sulindac to the active sulfide whereas oxidation to the sulfone is intact.