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Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine

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Summary

Nine extensive metabolizers (EMs) and eight poor metabolizers (PMs) of sparteine took a single oral dose of 100 mg of desipramine HCI before and while taking paroxetine 20 mg per day.

Before paroxetine, the median of the total desipramine clearance was 7 times higher in EMs than in PMs (102 and 15 l·h−1 respectively). This confirms that desipramine is extensively metabolized via the sparteine/debrisoquine oxidation polymorphism i.e. by CYP2D6. During paroxetine, the median clearances were 22 l·h−1 and 18 l·h−1 in EMs and PMs respectively. The 5-fold decrease in clearance in EMs when desipramine was co-administered with paroxetine confirms that paroxetine is a potent inhibitor of CYP2D6. The lack of effect on clearance in PMs shows that paroxetine is a selective inhibitor of CYP2D6, which is absent from the livers of PMs. Before paroxetine, the median of desipramine clearance via 2-hydroxylation was 40-times higher in EMs than in PMs (56 and 1.4 l·h−1 respectively), but during paroxetine, it was only 2-times higher (6 and 2.9 l·h−1 respectively). The increase in this clearance in PMs suggests that paroxetine is an inducer of the alternative, unidentified P 450(s) which catalyze(s) the formation of 2-OH-desipramine in this phenotype.

Before paroxetine, the median amounts of 2-OH-desipramine glucuronide recovered in urine were 69% and 68% of the total recovery of 2-OH-desipramine in urine in EMs and PMs respectively. During paroxetine, the corresponding values were 77% and 84%. This increase in the relative recovery of the glucuronide was statistically significant in both phenotypes, suggesting that paroxetine is a weak inducer of the glucuronidation of 2-OH-desipramine.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, Odense, Denmark

    K. Brøsen, K. K. Nielsen, S. H. Sindrup & L. F. Gram

  2. Odense Drug Evaluation Center (ODEC), Odense, Denmark

    K. Brøsen, J. G. Hansen, S. H. Sindrup & L. F. Gram

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  1. K. Brøsen
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  2. J. G. Hansen
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  3. K. K. Nielsen
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  4. S. H. Sindrup
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  5. L. F. Gram
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Brøsen, K., Hansen, J.G., Nielsen, K.K. et al. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 44, 349–355 (1993). https://doi.org/10.1007/BF00316471

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  • DOI: https://doi.org/10.1007/BF00316471

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