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In the first of two successive studies, four healthy male subjects received 500 mg of 14C-labeled imipenem alone and together with 500 mg of unlabeled cilastatin sodium. In the second study, the same subjects were given 250 mg of 14C-labeled cilastatin sodium alone and together with 250 and 1,000 mg of cold imipenem. Concentrations of imipenem and cilastatin in plasma, urine, and feces were assayed by high-pressure liquid chromatography and radiometry. Plasma concentrations of imipenem assayed radiometrically were higher than those measured by high-pressure liquid chromatography. In one subject studied at the end of drug administration, the open lactam metabolite of imipenem represented 9% of the radioactivity. Plasma levels of cilastatin determined by high-pressure liquid chromatography and radiometry were virtually identical. Urinary recovery of imipenem varied between 12 and 42% of the dose when that drug was given alone but increased to between 64 and 75% when administered with cilastatin sodium at a 1:1 ratio. Almost all radioactivity of imipenem was recovered in the urine within 96 h after drug administration. The open lactam metabolite, resulting from the metabolism of imipenem in the kidneys by a dipeptidase, dehydropeptidase-I, represented 80 to 90% of the effluent radioactivity when imipenem was given alone and about 20% when cilastatin sodium was coadministered. Renal excretion of cilastatin followed closely that of imipenem. Almost all of the administered radioactivity was recovered in 24 h, and about 75% of the dose was recovered as unchanged cilastatin within 6 h. The N-acetyl metabolite of cilastatin was found to represent about 12% of the total radioactivity.

Imipenem/cilastatin sodium consists of imipenem, a broad-spectrum carbapenem antimicrobial agent, and cilastatin sodium, an inhibitor of dehydropeptidase I, the renal enzyme that catalyzes the metabolism of imipenem. When imipenem is administered alone by the intravenous route, the levels excreted in the urine are low and variable (6%–38% of the dose) between subjects. Kinetics of imipenem in plasma are less variable, and the half-life of imipenem in plasma is 1 hr. When imipenem is coadministered with an equal amount of cilastatin, the amount of imipenem excreted in the urine represents 70% of the plasma clearance and the plasma half-life remains at 1 hr. Whether administered alone or with imipenem, the urinary excretion of cilastatin is 70%–80% of the dose administered, and its plasma half-life is also 1 hr. Thus, the pharmacokinetics of both agents are linear across the therapeutic dose range, and no accumulation of these agents occurs for therapeutic regimens. Decreases in renal function slow the elimination of both compounds and require a reduction in dosage when the glomerular filtration rate is less than 30 ml/min per 1.73 m2.