Metabolic profile of thiopental and cytochrome P450-mediated drug interactions in rats.

Abstract

1. Pentobarbital (PTB) is metabolised by cytochrome P450 (CYP) enzymes, being a model compound for evaluating CYP-mediated drug-drug interactions, has become difficult to obtain for animal studies in Japan. The metabolic pathway of thiopental (TP), a barbiturate with similar pharmacological properties, remains insufficiently characterised. This study investigated TP metabolic profile, with emphasis on CYP modulator-induced drug-drug interactions.2. TP was administered intraperitoneally to either phenobarbital (PB), chloramphenicol (CP)-pretreated, or untreated rats. Plasma TP concentrations were quantified using HPLC-DAD and a plate reader. Hypnotic and sedative properties were assessed by time to loss of righting reflex and recovery from hindlimb paralysis. TP metabolism was further evaluated in vitro using rat liver microsomes (RLMs) and recombinant CYP enzymes, and hepatic CYP mRNA levels were quantified by real-time RT-PCR.3. Compared with TP alone, PB pretreatment shortened TP-induced anaesthesia and decreased plasma TP concentrations, whereas CP pretreatment prolonged the duration of action and increased plasma TP levels. TP metabolism was mediated by CYP2B1 and CYP2C11. PB pretreatment induced CYP2B1 and enhanced TP metabolism, whereas CP pretreatment suppressed CYP2C11, inhibited CYP2B1, and reduced TP metabolism.4. These results suggest that TP is a useful alternative model compound for investigating pharmacokinetics/pharmacodynamics and CYP-mediated drug-drug interactions.