INFLUENCE OF DEXMEDETOMIDINE AND CLONIDINE ON HUMAN LIVER MICROSOMAL ALFENTANIL METABOLISM

Perioperative administration of the alpha-2 agonist clonidine has been shown to increase plasma alfentanil concentrations; however, the mechanism for this pharmacokinetic drug interaction is unknown. Because alfentanil undergoes extensive hepatic biotransformation, clonidine inhibition of alfentanil metabolism may alter alfentanil disposition. The first purpose of this investigation was to test the hypothesis that clonidine impairs human liver alfentanil metabolism. The new highly selective alpha-2 agonist dexmedetomidine (D-medetomidine) is a substituted imidazole and thus may inhibit hepatic drug biotransformation. The second purpose of this study, therefore, was to assess the effect of D-medetomidine and its levo (L) isomer on alfentanil biotransformation. Human liver microsomal alfentanil metabolism was assessed in vitro using a gas chromatography-mass spectrometry assay. Clonidine, at concentrations as great as 10-mu-M (far exceeding therapeutic levels), had no significant effect on alfentanil oxidation. In contrast, D-medetomidine and its optical isomer L-medetomidine were potent inhibitors of human liver microsomal alfentanil metabolism. The concentration producing 50% inhibition (IC50) of alfentanil (10-mu-M) oxidation was 0.7-1.0 and 2.8-4.0-mu-M for D-medetomidine and L-medetomidine, respectively. Preincubation of D-medetomidine with microsomes did not enhance the inhibition of alfentanil metabolism. These results suggest that the increased alfentanil plasma concentrations and potentiation of alfentanil anesthesia associated with clonidine do not result from clonidine inhibition of alfentanil metabolism. D-medetomidine impairment of alfentanil metabolism, however, if present at therapeutic concentrations, may influence alfentanil disposition.