Pharmacokinetics in healthy subjects of FCE 22101 and its acetoxymethyl ester, FCE 22891: effect of co-administration of imipenem/cilastatin on the renal metabolism of FCE 22101

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Abstract
The pharmacokinetics of FCE 22101 were studied in eight healthy male subjects who received FCE 22101 intravenously alone or together with imipenem/cilastatin which was given to inhibit dehydropeptidase-I, a renal enzyme metabolizing penem and carbapenem antibiotics. The kinetics of FCE 22101 were also studied following oral administration of its acetoxymethyl ester, FCE 22891. For comparative purposes, the kinetics of imipenem and cilastatin, given alone or together with FCE 22101, were calculated. Intravenously administered FCE 22101 at a dose of 250 mg gave peak plasma concentrations of about 12mg/l and the plasma half-life was about 60 min. Co-administration of FCE 22101 with imipenem/cilastatin did not affect the plasma kinetics of FCE 22101, nor did FCE 22101 influence the kinetics of imipenem or cilastatin. Cilastatin increased the urinary recovery of FCE 22101 from 17·5% to 53·0% with FCE 22101 alone to 73·2% to 91·8% when it was given with cilastatin. There was a high correlation between the urinary recovery of FCE 22101 in this study and that of imipenem given alone to the same subjects in previous studies; subjects who were high metabolizers of imipenem were also high metabolizers of FCE 22101. When FCE 22891 was given orally at a dose of 500 mg (corresponding to 400 mg of FCE 22101 free acid), peak concentrations of 2·2 to 6·1 mg/l were found. The absorption was rapid with peak concentrations achieved 20 to 80 min after administration. In comparison with imipenem, FCE 22101 seems to undergo less non-renal metabolism.