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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...

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An open, randomized, six-way crossover study was conducted in 12 healthy males to assess pharmacokinetics and bioinversion of ibuprofen enantiomers. The mean plasma terminal half-life (t1/2) of R(-)ibuprofen was 1.74 hr when intravenously infused as a racemic mixture and was 1.84 hr when intravenously infused alone. The mean t1/2 of S(+)ibuprofen was 1.77 hr when dosed as S(+)ibuprofen. Examination of values of both the absorption and disposition parameters of R(-)ibuprofen revealed that the kinetics of R(-)ibuprofen were not altered by concurrent administration of S(+)ibuprofen. In this study, there was little or no presystemic inversion of R(-)ibuprofen to its S(+)isomer. Also, 69% of the intravenous dose of R(-)ibuprofen was systemically inverted and 57.6% of the oral dose of R(-)ibuprofen lysinate was bioavailable as S(+)ibuprofen. These results indicate that the bioinversion of R(-)ibuprofen administered orally is mainly systemic. Because bioinversion of R(-)ibuprofen is not complete, S(+)ibuprofen produced higher bioavailability of S(+)ibuprofen (92.0%) than either racemic ibuprofen (70.7%) or R(-)ibuprofen (57.6%). However, bioavailability of R(-)ibuprofen (83.6%) when dosed alone was not significantly different from when dosed as racemic mixture (80.7%).