Relationship of cytochrome P450 pharmacogenetics to the effects of yohimbine on gastrointestinal transit and catecholamines in healthy subjects.
Alpha-2 adrenergic receptors tonically inhibit colonic motility and the alpha(2)-adrenergic antagonist yohimbine, given intravenously, increased colonic tone in humans. However, the effect of yohimbine on colonic transit in humans is unknown. In this study, 30 healthy volunteers were randomized to yohimbine 16.2 mg p.o. t.i.d. or identical placebo for 7 days. We evaluated gastric emptying, small intestinal, and colonic transit by scinitigraphy, bowel habits, haemodynamics and plasma catecholamines. As cytochrome P450 enzymes metabolize yohimbine, P450 genotypes (CYP2D6 and CYP3A4) were determined in 25 of 30 subjects who consented to genetic studies. The relationship between drug metabolizer status predicted by CYP2D6 and CYP3A4 and effects of yohmibine were assessed. Compared to placebo, yohimbine increased (P < or = 0.02) diastolic blood pressure, plasma noradrenaline concentrations and maximum tolerated volume during the satiation test [yohimbine (1241 +/- 88, mean +/- SEM) vs placebo (1015 +/- 87), P = 0.054]. However, yohimbine did not affect gastrointestinal transit. Based on CYP2D6 and CYP3A4 alleles, seven and 18 subjects were, respectively, extensive (EM) and poor (PM) metabolizers of yohimbine. Compared to EM, PM of yohimbine had a greater increase in plasma noradrenaline (P = 0.1 for PM vs EM), lower maximum tolerated volumes (1120 +/- 95 vs 1484 + 131 mL, P = 0.02), and faster colonic transit (i.e. GC(24) was 3.0 +/- 0.4 vs 2.1 +/- 0.5, P = 0.1). These data suggest that CYP2D6 and CYP3A4 genotypes which determine the metabolism of yohimbine may influence its sympathetic and gastrointestinal effects.
Bharucha
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Clinical and Enteric Neuroscience Translational and Epidemiological Research Program (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, MN 55905, USA. bharucha.adil@mayo.edu
Skaar
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Andrews
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CN
Camilleri
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M
Philips
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Seide
B
B
Burton
D
D
Baxter
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K
Zinsmeister
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D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D002395:Catecholamines / Q000097:blood*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003672:Defecation / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D005772:Gastrointestinal Transit / Q000187:drug effects*; D005838:Genotype; D006439:Hemodynamics; D006801:Humans; D010597:Pharmacogenetics; D010919:Placebos; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D012527:Satiation / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D010919:Placebos; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human