Dose-dependent kinetics of cilastatin in laboratory animals.

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Lin JH, Chen IW, Ulm EH

Dose-dependent kinetics of cilastatin in laboratory animals.

Drug Metab Dispos. 1989 Jul-Aug;17(4):426-32.

PubMed ID

2571484 [ View in PubMed

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Abstract

Cilastatin, a potent inhibitor of renal dehydropeptidase I, was specifically designed to inhibit renal metabolism of the antibiotic imipenem in order to achieve therapeutically relevant imipenem concentrations in the urinary tract. In this study the elimination kinetics of cilastatin in rats at doses of 5, 10, 20, 50, 100, and 200 mg/kg iv were demonstrated to be dose dependent, with total plasma clearance and non-renal clearance falling from 20.2 +/- 3.1 ml/min/kg and 17.7 +/- 3.3 ml/min/kg (mean +/- S.D.) at the 5 mg/kg dose to 11.4 +/- 1.2 ml/min/kg and 5.30 +/- 1.2 ml/min/kg, respectively, at the 200 mg/kg dose, whereas the volume of distribution of the drug remained unchanged. Since cilastatin is mainly eliminated by renal excretion as well as by N-acetylation, the non-renal clearance may reasonably reflect the N-acetylation process. Thus, the dose-dependent kinetics of cilastatin might be explained, at least partly, by the saturation of the N-acetylation of the drug. The dose-related decrease in the fraction (fm) of cilastatin converted to its N-acetylated metabolite provided further evidence for the saturable N-acetylation. The fm values decreased from 0.915 at the 10 mg/kg dose to 0.626 at the 100 mg/kg dose. Although both the total plasma clearance and non-renal clearance decreased with increasing dose, the dose had an opposite effect on the renal clearance of cilastatin. The renal clearance of cilastatin increased from 2.50 +/- 0.40 ml/min/kg at the lowest dose to 6.10 +/- 0.50 ml/min/kg at the highest dose as the dose increased.(ABSTRACT TRUNCATED AT 250 WORDS)

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cilastatin	Dipeptidase 1	Protein	Humans	Yes	Inhibitor	Details