Effect of Induction and Inhibition of Drug Metabolism on Pharmacokinetics and Anticoagulant Activity of the Enantiomers of Phenprocoumon in Rats

Abstract

The elimination, distribution and anticoagulant activities of the enantiomers of phenprocoumon were studied in rats following enzyme induction by phenobarbital (pretreatment with 75 mg·kg^–1 for 4 days) and enzyme inhibition by chloramphenicol (100 mg·kg^–1 1 h prior to the injection of phenprocoumon and then 50 mg·kg^–1 every 12 h). Pretreatment with phenobarbital increased the rate of elimination and decreased the total anticoagulant effect per dose of both enantiomers. It also caused a slight reduction of the liver/plasma concentration ratio of the enantiomers due to the increase of the liver weight and a significant enhancement of the synthesis rate of prothrombin complex activity in non-anticoagulated rats. Chloramphenicol decreased the rate of elimination and enhanced the total anticoagulant effect per dose of both enantiomers. The distribution between plasma and liver remained unaffected. Thus, in rats neither the induction of the phenprocoumon metabolism by phenobarbital nor its inhibition by chloramphenicol appears to be stereoselective.

Mephenytoin stereoselective elimination in the rat: III. Stereoselective time course of induction during chronic hepatic portal vein administration

“…Since enzyme induction can alter the relative composition of enzymes within this class, it appears likely that it may also produce changes in stereoselective drug disposition. Currently, there is limited information on the impact of enzyme induction on stereoselective drug clearance (4)(5)(6)(7)(8). Yet, many racemic drugs are composed of enantiomers which display differences in pharmacologic and/or toxicologic activity (9)(10)(11)(12).…”