Human sympathetic activation by α 2-adrenergic blockade with yohimbine: Bimodal, epistatic influence of cytochrome P450-mediated drug metabolism

Pascal Le Corre, Robert J. Parmer, Mala T. Kailasam, Brian P. Kennedy, Todd P. Skaar, Herbert Ho, Roger Leverge, Douglas W. Smith, Michael G. Ziegler, Paul A. Insel, Nicholas J. Schork, David A. Flockhart, Daniel T. O'Connor

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36 Scopus citations

Abstract

Background α 2-Adrenergic blockade responses suggest adrenergic dysfunction in hypertension. α 2-Blockade is also used to treat autonomic dysfunction. However, pharmacokinetic determinants of yohimbine disposition are not understood. Methods We evaluated α 2-blockade with intravenous yohimbine in 172 individuals. Specific cytochrome P450 (CYP) isoform-mediated metabolism was investigated. Results were evaluated by ANOVA and by maximum likelihood analysis for bimodality of response distributions. Results Yohimbine metabolism to 11-hydroxy-yohimbine displayed greater than 1000-fold variability, with 17 individuals showing no metabolism. Nonmetabolizers differed from others in ethnicity but not in age, sex, body habitus, blood pressure, heart rate, or family history of hypertension. Bimodality of metabolism was suggested by frequency histogram, as well as maximum likelihood and cluster analysis. Among ethnic groups, subjects of European ancestry had the highest frequency of nonmetabolism. In vitro oxidation suggested that the major route of metabolism (lowest Michaelis-Menten constant and greatest intrinsic clearance) was likely via CYP2D6 to 11-hydroxy-yohimbine. In vivo genotypes at both CYP2D6 and CYP3A4 were necessary to predict metabolism (overall F = 3.03, P = .005); an interaction of alleles at these 2 loci (interaction F = 3.05, P = .033) suggested an epistatic effect on drug metabolism in vivo. Nonmetabolizers had greater activation of sympathetic nervous system activity. Yohimbine increased blood pressure, an effect mediated hemodynamically by elevation of cardiac output rather than systemic vascular resistance. Blood pressure and cardiac output responses did not differ by metabolizer group. Conclusions We conclude that heterogeneous, bimodally distributed yohimbine metabolism depends on common genetic variation in both CYP2D6 and CYP3A4 and contributes to differences in sympathetic neuronal response to α 2-blockade. These results have implications for both diagnostic and therapeutic uses of this α 2-antagonist.

Original languageEnglish (US)
Pages (from-to)139-153
Number of pages15
JournalClinical Pharmacology and Therapeutics
Volume76
Issue number2
DOIs
StatePublished - Aug 1 2004

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Le Corre, P., Parmer, R. J., Kailasam, M. T., Kennedy, B. P., Skaar, T. P., Ho, H., Leverge, R., Smith, D. W., Ziegler, M. G., Insel, P. A., Schork, N. J., Flockhart, D. A., & O'Connor, D. T. (2004). Human sympathetic activation by α 2-adrenergic blockade with yohimbine: Bimodal, epistatic influence of cytochrome P450-mediated drug metabolism. Clinical Pharmacology and Therapeutics, 76(2), 139-153. https://doi.org/10.1016/j.clpt.2004.04.010