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Kinetics of biotransformation of clonazepam to its 7-amino metabolite in the monkey

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Abstract

The pharmacokinetic behavior of the 7-amino metabolite of clonazepam administered exogenously and formed endogenously from the parent drug was studied in a group of rhesus monkeys using constant rate intravenous infusions. Plasma levels of the 7-amino metabolite and/or clonazepam were determined with a GC-CI-MS method. The biological half-life of the 7-amino metabolite (2.2 ± 1.0 hr) was shorter than that of clonazepam (4.9 ± 0.2 hr). Total body clearance of the metabolite (0.83 ± 0.16 liters/hr/kg) was larger than that of the parent drug (0.55 ± 0.09 liters/hr/kg). The kinetics of in vivo biotransformation were described by a two- compartment model in which formation and disposition of the metabolite follow first-order processes. The fraction of a dose of clonazepam appearing in the systemic circulation as 7-amino metabolite was 0.70 ± 0.30. This value may underestimate the actual fraction formed, if the metabolite is susceptible to first- pass metabolism following in situ formation.

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Author notes

  1. Allen A. Lai

    Present address: Clinical Research Department, Medical Division, Burroughs Wellcome Co., 27709, Research Triangle Park, North Carolina

Authors and Affiliations

  1. Departments of Pharmaceutical Sciences and Neurological Surgery, Schools of Pharmacy and Medicine, University of Washington, 98195, Seattle, Washington

    Allen A. Lai & Renè H. Levy

  2. Department of Biochemistry and Drug Metabolism, Hoffmann-La Roche, Inc., 07110, Nutley, New Jersey

    Bo H. Min & William A. Garland

Authors
  1. Allen A. Lai
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  2. Bo H. Min
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  3. William A. Garland
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  4. Renè H. Levy
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Additional information

This work was supported in part by NIH Research Contract No. N01-NS-1-2283 and Research Grant No. NS-04053 awarded by the National Institute of Neurological and Communicative Disorders and Strokes, PHS/OHEW.

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Lai, A.A., Min, B.H., Garland, W.A. et al. Kinetics of biotransformation of clonazepam to its 7-amino metabolite in the monkey. Journal of Pharmacokinetics and Biopharmaceutics 7, 87–95 (1979). https://doi.org/10.1007/BF01059443

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  • DOI: https://doi.org/10.1007/BF01059443

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