Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem.
1. The benzodiazepines are among the most frequently prescribed of all drugs and have been used for their anxiolytic, anticonvulsant, and sedative/hypnotic properties. Since absorption rates, volumes of distribution, and elimination rates differ greatly among the benzodiazepine derivatives, each benzodiazepine has a unique plasma concentration curve. Although the time to peak 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 benzodiazepines and in potential pharmacokinetic interactions between the benzodiazepines and other coadministered drugs is discussed. 3. Buspirone, an anxiolytic with minimal sedative effects, undergoes extensive metabolism, with hydroxylation and dealkylation being the major pathways. Pharmacokinetic interactions of buspirone with other coadministered drugs seem to be minimal. 4. Zopiclone and zolpidem are used primarily as hypnotics. Both are extensively metabolized; N-demethylation, N-oxidation, and decarboxylation of zopiclone occur, and zolpidem undergoes oxidation of methyl groups and hydroxylation of a position on the imidazolepyridine ring system. Zopiclone has a chiral centre, and demonstrates stereoselective pharmacokinetics. Metabolic drug-drug interactions have been reported with zopiclone and erythromycin, trimipramine, and carbamazepine. Reports to date indicate minimal interactions of zolpidem with coadministered drugs; however, it has been reported to affect the Cmax and clearance of chlorpromazepine and to decrease metabolism of the antiviral agent ritonavin. Since CYP3A4 has been reported to play an important role in metabolism of zolpidem, possible interactions with drugs which are substrates and/or inhibitors of that CYP isozyme should be considered.
Chouinard
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G
Louis-H. Lafontaine Hospital, Department of Psychiatry, University of Montreal, Quebec, Canada.
Lefko-Singh
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K
Teboul
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E
D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D053961:Azabicyclo Compounds; D001569:Benzodiazepines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D002065:Buspirone / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D010879:Piperazines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D000077334:Zolpidem
D014151:Anti-Anxiety Agents; D053961:Azabicyclo Compounds; D006993:Hypnotics and Sedatives; D010879:Piperazines; D011725:Pyridines; C515050:zopiclone; D001569:Benzodiazepines; D000077334:Zolpidem; D003577:Cytochrome P-450 Enzyme System; D002065:Buspirone