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

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 12 mg/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.

Pharmacokinetics of [14C]FCE 22891, a penem antibiotic, following oral administration to healthy volunteers

“…The pharmacokinetic parameters of FCE 22101 obtained in the present study after oral administration of its prodrug FCE 22891 are in good agreement with those reported previously (7,9,13). Recovery of radioactivity in this study was almost complete, because about 90 to 95% of the dose (3a).…”

“…This is in agreement with the limited intersubject variabilities in AUCs observed after intravenous administration of FCE 22101 (7,9,13). The variabilities in CLR and urinary excretion of FCE 22101 observed after intravenous administration reflect intersubject differences in the metabolic activity of renal DHP-I.…”

“…The identity of the radioactive species in plasma was not determined. However, significant levels of the metabolite P1 have been observed in plasma following oral administration of FCE 22891 to humans (6), whereas only traces of this metabolite have been detected after intravenous administration (7). The presence of this metabolite in plasma after oral administration might be due to the action of DHP-I in the human gut, the presence of which has recently been reported (11 (14).…”

“…The pharmacokinetics of FCE 22891 in humans have been studied following different single doses ranging from 500 mg to 2 g (7,9,12,13), following repeated administration of 500 mg to 1 g (1), and after food intake (9). Its absolute bioavailability as FCE 22101 is about 30 to 40% (7,9,13).…”

“…Its absolute bioavailability as FCE 22101 is about 30 to 40% (7,9,13). FCE 22891 is rapidly hydrolyzed to FCE 22101 in vivo; no detectable unchanged FCE 22891 is found in human plasma or urine, even when samples are collected over potassium fluoride to inhibit ex vivo hydrolysis (12).…”