N-Formimidoyl thienamycin (MK0787) undergoes renal metabolism by a dipeptidase, dehydropeptidase I, located on the brush border of the proximal tubular cells. The effects of two inhibitors (MK-789 and MK-791) of dehydropeptidase I on the pharmacokinetics of N-formimidoyl thienamycin were studied in 41 healthy subjects receiving various combinations of N-formimidoyl thienamycin and MK-789 or MK-791. Both inhibitors affected the plasma kinetics of N-formimidoyl thienamycin only to a small extent. Plasma concentrations and the area under the plasma concentration curve increased about 20%'o with a proportional decrease in plasma clearance. Plasma half-life was not altered significantly. Coadministration of MK-789 or MK-791 resulted in uniform and marked increases in urinary recovery and renal clearance of N-formimidoyl thienamycin. Thus, at an Nformimidoyl thienamycin/MK-791 ratio of 1:0.25 or higher, the urinary recovery was about 72% in all subjects, whereas it varied between 7.7 and 43% when Nformimidoyl thienamycin was given alone. The ratio of the N-formimidoyl thienamycin and MK-791 doses affected response. At relatively higher doses of MK-791, significant increases of N-formimidoyl thienamycin urinary recovery, renal clearance, and urine concentrations occurred during the later part of the 10-h observation period after each administration. At a 1:1 ratio of the two drugs, the inhibition of renal metabolism of N-formimidoyl thienamycin was maintained for at least 8 h, whereas renal clearance declined as soon as 4 h after the administration of a 1:0.25 ratio. The results indicated that MK-789 and MK-791 alter the renal excretion of N-formimidoyl thienamycin from glomerular filtration plus tubular secretion to glomerular ifitration only, possibly by competitively inhibiting the penetration of N-formimidoyl thienamycin into the proximal tubular cells.The human pharmacokinetics of N-formimidoyl thienamycin (MK0787) are characterized by high plasma concentrations and rapid elimination via the kidneys (3). The urinary recovery (UR) of N-formimidoyl thienamycin varies considerably between subjects, whereas the withinsubject variation is very small (3). The were included in the studies described in this report.All subjects gave their informed written consent to participate, and the protocols for the studies were 300

Three new angiotensin converting-enzyme inhibitors were given orally to 20 men in single doses ranging from 1.25 to 40 mg. Two of them induced comparable marked inhibition of both the blood pressure response to exogenous angiotensin I and plasma converting-enzyme activity. Onset of action was relatively slow, but 21 to 24 hr after drug plasma converting-enzyme activity was still clearly reduced. The third was less active. There was a close correlation between blood pressure response on administration of angiotensin I and plasma converting-enzyme activity. There were no adverse effects. These new drugs are interesting because of their long duration of action. The measurement of plasma converting-enzyme activity seems useful for monitoring efficacy of converting-enzyme blockade and compliance to therapy.

The pharmacokinetics of intravenously administered N-formimidoyl thienamycin (MK0787) were studied in 14 healthy male subjects in a single-dose study, in which the volunteers received N-formimidoyl thienamycin with and without probenecid, and in a multiple-dose study, in which the subjects were given 250 or 500 mg every 8 h for 10 doses. High dose-related plasma concentrations of Nformimidoyl thienamycin were achieved; co-administration with probenecid resulted in only minor increases in these concentrations. No accumulation in plasma was seen after multiple doses. The plasma half-life of N-formimidoyl thienamycin was slightly less than 1 h and did not increase significantly with the coadministration of probenecid. The urinary recovery of N-formimidoyl thienamycin varied between 6.0 and 38.4% of the dose with a marked intersubject variability. Variations in individual subjects were small, however, when the urinary recoveries after repeated doses were compared. These results were in agreement with previous animal studies showing a renal metabolism of Nformimidoyl thienamycin. Probenecid administration resulted in a marked decrease in N-formimidoyl thienamycin urinary recovery. In vitro experiments showed that the decay of N-formimidoyl thienamycin in spiked pretreatment urine samples was 2 to 5%/h with more rapid degradation at acidic than at basic pH. N-Formimidoyl thienamycin (MK0787) is a stable derivative of thienamycin, a carbapenem antibiotic produced by Streptomyces cattleya (5). Its antibacterial spectrum is unusually broad and includes many commonly antibiotic-resistant bacterial species, e.g., Pseudomonas aeruginosa and enterococci (2, 3, 9). The antibacterial activity is bactericidal, and N-formimidoyl thienamycin is extremely resistant to degradation by bacterial P-lactamases (1,8).In animals, N-formimidoyl thienamycin is rapidly excreted via the kidneys (3). However, urinary recovery varies with the species, and a renal metabolism of N-formimidoyl thienamycin has been demonstrated. The present studies were undertaken to investigate the pharmacokinetics of N-formimidoyl thienamycin in healthy volunteers after the administration of single doses (with or without the prior administration of probenecid) and after multiple doses.(These studies were presented at the 21st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 111., 1981.) MATERIALS AND METHODS Subjects. Fourteen healthy male Caucasian subjects were recruited for the two studies. The mean age was 22 years (range, 19 to 28 years), and the mean body weight was 71.6 kg (range, 62.3 to 77.4 kg). Written informed consent was obtained, and the studies were approved by the Ethical Committee at

In the first of two successive studies, four healthy male subjects received 500 mg of "4C-labeled imipenem alone and together with 500 mg of unlabeled cilastatin sodium. In the second study, the same subjects were given 250 mg of "4C-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 is a carbapenem antibiotic with a broad antibacterial spectrum, including enterococci, Pseudomonas aeruginosa, and Bacteroidesfragilis (4, 7). In animals, imipenem has been found to be excreted renally but also to be metabolized in the kidneys by a dipeptidase, dehydropeptidase I (DHP-I), located on the brush border of the proximal tubular cells (4). Similar metabolism occurs in humans, resulting in variable urinary recovery (5 to 40% of the administered imipenem doses) with a marked intersubject but a minimal intrasubject variability (6). This metabolism is inhibited by cilastatin, an inhibitor of DHP-I (3). In humans, coadministration of imipenem with cilastatin sodium results in an increase of the urinary recovery of imipenem to about 70% of the dose, irrespective of the degree of metabolism when imipenem is given alone (5). It has been suggested that the imipenem which cannot be recovered in the urine undergoes systemic metabolism (5, 6). The present investigation was undertaken to elucidate the metabolic disposition and excretion of imipenem and cilastatin by using radiolabeled imipenem or cilastatin sodium.MATERIALS AND METHODS Both studies described here were approved by the Ethical Review Committee and the Isotope Committee of the Faculty of Medicine, University of Umea, Ume'a, Sweden, and all volunteers gave written, informed...