The pharmacokinetics of imipenem were evaluated in four studies involving 49 healthy men, several of whom participated in more than one study. Within a dose-range of 150 to 1000 mg, imipenem was found to give high plasma concentrations, proportional to the size of the dose. The half life in the beta-phase was about 1 h in 48 subjects with normal renal function and about 80 min in one subject with a glomerular filtration rate (GFR) of about 50 ml/min/1 X 73 m2. The volume of distribution in the central compartment was about 101. Co-administration of imipenem with probenecid resulted in a slight but significant increase of the plasma half life and a corresponding increase of the area under the plasma concentration curve (AUC). The renal excretion of imipenem was characterized by low urinary recovery (UR) of imipenem. That was in agreement with findings by others that in animals, imipenem undergoes renal metabolism by a dipeptidase, dehydropeptidase I, located to the brush border of the proximal tubular cells. There was a very high degree of between-subject variability of the UR with values varying from about 5% to more than 40% of the dose. Comparing the results obtained after several administrations of imipenem to the same subjects, a small within-subject variability was found. Co-administration of imipenem with inhibitors of the dehydropeptidase MK0789 or MK0791 (cilastatin), resulted in a uniform increase of the imipenem UR to about 70% of the dose irrespective of the degree of metabolism when imipenem was given alone. The effects of the inhibitors on the plasma kinetics of imipenem were an increase of the AUC by about 20% and a proportional decrease of the plasma clearance (VClp) while the plasma half life remained unaffected. Testing various ratios of imipenem and the inhibitors and using incremental data, it could be demonstrated that an increase of the imipenem/cilastatin ratio resulted in a prolonged inhibition of the renal metabolism. Optimal inhibition seemed to be achieved at a ratio of 1:1 between imipenem and cilastatin. A practical consequence of the inhibition of renal metabolism by cilastatin was that high urine concentrations were maintained for longer periods when the combination was given than when imipenem was administered alone. In all subjects, imipenem and the inhibitors were well tolerated and the only adverse reaction observed was nausea during infusion, observed in one subject.