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Clinical Pharmacokinetics of Chlordiazepoxide

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Summary

Chlordiazepoxide was the first benzodiazepine derivative made available for clinical use. The metabolic pathway of chlordiazepoxide is complex, since the drug is biolransformed into a succession of pharmacologically active products: desmethylchlordiazepoxide, demoxepam, desmethyldiazepam, and oxazepam. The elimination half-life (t1/2β) chlordiazepoxide following single doses in healthy individuals generally ranges from 5 to 30 hours, and the volume of distribution from 0.25 to 0.50 liters/kg. The hepatic extraction ratio is well under 5 %. Elimination of the parent compound is mirrored by formation of the first active metabolite.

Clearance of chlordiazepoxide is reduced and (t1/2β) is prolonged in the elderly, in those with cirrhosis, and in those receiving concurrent disulfiram therapy. Oral chlordiazepoxide is rapidly and completely absorbed, but intramuscular injection is painful and results in slow and erratic absorption. Multiple-dose therapy with chlordiazepoxide results in accumulation of the parent compound, as well as two or more of its active metabolites. The rate and extent of accumulation varies considerably between individuals.

A relation between plasma concentrations of chlordiazepoxide and its metabolites to clinical effects has been suggested in some studies and is currently under further investigation.

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Authors and Affiliations

  1. Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA

    David J. Greenblatt

  2. Psychopharmacology Research Laboratory, Massachusetts Mental Health Center, Boston, Massachusetts, USA

    Richard I. Shader & Stuart M. MacLeod

  3. Clinical Institute, Addiction Research Foundation, Toronto, Ontario, USA

    Edward M. Sellers

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  1. David J. Greenblatt
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  2. Richard I. Shader
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  3. Stuart M. MacLeod
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  4. Edward M. Sellers
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Greenblatt, D.J., Shader, R.I., MacLeod, S.M. et al. Clinical Pharmacokinetics of Chlordiazepoxide. Clin Pharmacokinet 3, 381–394 (1978). https://doi.org/10.2165/00003088-197803050-00004

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