Human sympathetic activation by alpha2-adrenergic blockade with yohimbine: Bimodal, epistatic influence of cytochrome P450-mediated drug metabolism.
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Le Corre P, Parmer RJ, Kailasam MT, Kennedy BP, Skaar TP, Ho H, Leverge R, Smith DW, Ziegler MG, Insel PA, Schork NJ, Flockhart DA, O'connor DT
Human sympathetic activation by alpha2-adrenergic blockade with yohimbine: Bimodal, epistatic influence of cytochrome P450-mediated drug metabolism.
Clin Pharmacol Ther. 2004 Aug;76(2):139-53. doi: 10.1016/j.clpt.2004.04.010.
- PubMed ID
- 15289791 [ View in PubMed]
- Abstract
BACKGROUND: alpha2-Adrenergic blockade responses suggest adrenergic dysfunction in hypertension. alpha2-Blockade is also used to treat autonomic dysfunction. However, pharmacokinetic determinants of yohimbine disposition are not understood. METHODS: We evaluated alpha2-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 alpha2-blockade. These results have implications for both diagnostic and therapeutic uses of this alpha2-antagonist.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Yohimbine Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails Yohimbine Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails