Metabolism of anxiolytics and hypnotics: Benzodiazepines, buspirone, zoplicone, and zolpidem

1. The benzodiazepines are among the most frequently prescribed of all drug s and have been used for their anxiolytic, anticonvulsant, and sedative/hyp notic properties. Since absorption rates, volumes of distribution, and elim ination rates differ greatly among the benzodiazepine derivatives, each ben zodiazepine has a unique plasma concentration curve. Although the time to p eak plasma levels provides a rough guide, it is not equivalent to the time to clinical onset of effect. The importance of alpha and beta half-lives in the actions of benzodiazepines is discussed. 2. The role of cytochrome P450 isozymes in the metabolism of benzodiazepine s and in potential pharmacokinetic interactions between the benzodiazepines and other coadministered drugs is discussed. 3. Buspirone, an anxiolytic with minimal sedative effects, undergoes extens ive metabolism, with hydroxylation and dealkylation being the major pathway s. Pharmacokinetic interactions of buspirone with other coadministered drug s seem to be minimal. 4. Zopiclone and zolpidem are used primarily as hypnotics. Both are extensi vely metabolized; N-demethylation, N-oxidation, and decarboxylation of zopi clone occur, and zolpidem undergoes oxidation of methyl groups and hydroxyl ation of a position on the imidazolepyridine ring system. Zopiclone has a c hiral centre, and demonstrates stereoselective pharmacokinetics. Metabolic drug-drug interactions have been reported with zopiclone and erythromycin, trimipramine, and carbamazepine. Reports to date indicate minimal interacti ons of zolpidem with coadministered drugs; however, it has been reported to affect the C-max and clearance of chlorpromazepine and to decrease metabol ism of the antiviral agent ritonavin. Since CYP3A4 has been reported to pla y an important role in metabolism of zolpidem, possible interactions with d rugs which are substrates and/or inhibitors of that CYP isozyme should be c onsidered.