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

Background α2‐adrenergic blockade responses suggest adrenergic dysfunction in hypertension. α2‐blockade is also used to treat autonomic dysfunction. However, pharmacokinetic determinants of yohimbine disposition are not understood. Methods We evaluated α2‐blockade with intravenous yohimbine. Specific cytochrome P‐450 isoform‐mediated metabolism was investigated. Results were evaluated by analysis of variance, and by maximum likelihood analysis for bimodality of response distributions. Results Yohimbine metabolism to 11‐OH‐yohimbine displayed >1000‐fold variability, with n=17 individuals showing no metabolism. Bimodality of metabolism was suggested by maximum likelihood analysis. In vitro oxidation suggested that the major route of metabolism 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=0.005); an interaction of alleles at these two loci ( interaction F=3.05, p=0.033) suggested an epistatic effect on drug metabolism. Non‐metabolizers had greater activation of sympathetic nervous system activity. 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 α2‐blockade. These results have implications for both diagnostic and therapeutic uses of this α2‐antagonist. Clinical Pharmacology & Therapeutics (2005) 77 , P6–P6; doi: 10.1016/j.clpt.2004.11.024