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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%).

The pharmacokinetics of 250 mg each of intravenous imipenem and cilastatin in combination and 250 mg of cilastatin alone were studied in subjects with varying degrees of renal clearance. Renal disease did not change the volume of distribution of either drug. When the glomerular filtration rate was greater than 100 ml per minute, 48.6 percent of imipenem and 57.1 percent of cilastatin were recovered unchanged in the urine. Consequently, as the glomerular filtration rate declined, the half-life of imipenem increased from 1.02 hours in normal subjects to 3.69 hours in those undergoing dialysis. For cilastatin, the comparable values were 0.86 and 17.08 hours, respectively. The kinetics of cilastatin were unaffected by imipenem. The greater effect of renal disease on the half-life of cilastatin was due to a concomitant 87 percent reduction in nonrenal clearance. Both drugs were removed by hemodialysis. Dialysis reduced the half-life of imipenem from 4.80 to 2.45 hours and that of cilastatin from 16.63 to 3.86 hours. Therefore, dose adjustments will be required in patients with markedly reduced renal function and supplemental dosing will be required after hemodialysis.

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.