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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vivo CYP3A4 Heteroactivation Is a Possible Mechanism for the Drug Interaction between Felbamate and Carbamazepine

Ann-Charlotte Egnell, Brian Houston and Scott Boyer
Journal of Pharmacology and Experimental Therapeutics June 2003, 305 (3) 1251-1262; DOI: https://doi.org/10.1124/jpet.102.047530
Ann-Charlotte Egnell
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Brian Houston
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Scott Boyer
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Abstract

Atypical (non-Michaelis-Menten) kinetics are commonly observed with CYP3A4 substrates in vitro. If relevant in vivo, cytochrome P450 heteroactivation could give rise to increased drug clearance. To test the possible in vivo relevance of atypical cytochrome P450 kinetics, we investigated the role of heteroactivation in the therapeutically relevant drug interaction between the anti-epileptics felbamate and carbamazepine. Felbamate heteroactivates CYP3A4-mediated formation of carbamazepine-10,11-epoxide (carbamazepine-ep), the major metabolite of carbamazepine, in human liver microsomes and recombinant CYP3A4 at relevant in vivo concentrations of both drugs (maximum activation 98% at 10 μM carbamazepine, 1 mM felbamate). Felbamate (50–500 μM) did not induce CYP3A4, as based on mRNA measurements in human liver slices. The further metabolism of carbamazepine-ep was inhibited (38% by 500 μM felbamate) in human liver slices. We propose a methodology to predict changes in steady-state plasma concentrations (Css) of parent drug and metabolite from in vitro heteroactivation and inhibition data, including prediction of the increase in fraction metabolized. A meta-analysis of reported in vivo effects of felbamate on Csscarbamazepine was performed to allow evaluation of this approach. The predicted effect of in vitro heteroactivation on Csscarbamazepine corresponds well to that observed in vivo. Combining the effect of heteroactivation on the fraction metabolized to carbamazepine-ep, and inhibition of its further metabolism, predicts a change in Csscarbamazepine-ep that falls within the range observed in vivo. Our results strongly suggest that in vivo heteroactivation of CYP3A4 is a possible mechanism of the clinically observed drug interaction between felbamate and carbamazepine.

Footnotes

  • This work was presented in part at EUFEPS 2002 New Safe Medicines Faster, 2002 October 20–23, Stockholm, Sweden and at ISSX 11th North American Meeting, 2002 Oct 27–31, Orlando, FL.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.102.047530.

  • ABBREVIATIONS: P450, cytochrome P450; CssCBZ, CssCBZ-ep, plasma steady-state concentration of carbamazepine and of carbamazepine-10,11-epoxide, respectively; carbamazepine-diol, carbamazepine-trans-diol (trans-10,11-dihydro-10,11-dihydroxycarbamazepine); carbamazepine-ep, carbamazepine-10,11-epoxide; HLM, human liver microsomes; huPO, human acidic ribosomal phosphoprotein; rCYP, recombinantly expressed P450; DMF, dimethyl formamide; DMSO, dimethyl sulfoxide; HPLC, high performance liquid chromatography; PCR, polymerase chain reaction; TAMRA, tetramethylrhodamine.

    • Received December 4, 2002.
    • Accepted January 10, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 3
1 Jun 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vivo CYP3A4 Heteroactivation Is a Possible Mechanism for the Drug Interaction between Felbamate and Carbamazepine

Ann-Charlotte Egnell, Brian Houston and Scott Boyer
Journal of Pharmacology and Experimental Therapeutics June 1, 2003, 305 (3) 1251-1262; DOI: https://doi.org/10.1124/jpet.102.047530

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vivo CYP3A4 Heteroactivation Is a Possible Mechanism for the Drug Interaction between Felbamate and Carbamazepine

Ann-Charlotte Egnell, Brian Houston and Scott Boyer
Journal of Pharmacology and Experimental Therapeutics June 1, 2003, 305 (3) 1251-1262; DOI: https://doi.org/10.1124/jpet.102.047530
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