Neal L Benowitz1, Andy Z X Zhu, Rachel F Tyndale, Delia Dempsey, Peyton Jacob. 1. Department of Medicine, Bioengineering and Therapeutic Sciences, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, California 94143-1220, USA. nbenowitz@medsfgh.ucsf.edu
Abstract
BACKGROUND: Bupropion, an antidepressant and smoking cessation medication, is metabolized to hydroxybupropion (HB), an active metabolite, primarily by CYP2B6. OBJECTIVES: To compare plasma concentrations of bupropion and metabolites at steady state in healthy volunteers with and without CYP2B6 genetic variants. METHODS: In a genotype-guided study of 42 healthy individuals, we measured the plasma and urine concentrations of bupropion and its metabolites, HB, threohydrobupropion, and erythrohydrobupropion after 7 days of sustained-release bupropion dosing. RESULTS: CYP2B6*6 and *18 gene variants were associated with ~33% reduced concentrations of HB, with no effects on concentrations of bupropion or other metabolites. We could account for 50% of the variation in HB concentrations in a model including genotype and sex. CONCLUSION: As HB is active and its steady-state concentrations are more than 10 times higher than bupropion, CYP2B6 variants are likely to affect pharmacological activity. Because of the large individual variation within the genotype group, the use of therapeutic drug monitoring for dose optimization may be necessary.
BACKGROUND:Bupropion, an antidepressant and smoking cessation medication, is metabolized to hydroxybupropion (HB), an active metabolite, primarily by CYP2B6. OBJECTIVES: To compare plasma concentrations of bupropion and metabolites at steady state in healthy volunteers with and without CYP2B6 genetic variants. METHODS: In a genotype-guided study of 42 healthy individuals, we measured the plasma and urine concentrations of bupropion and its metabolites, HB, threohydrobupropion, and erythrohydrobupropion after 7 days of sustained-release bupropion dosing. RESULTS:CYP2B6*6 and *18 gene variants were associated with ~33% reduced concentrations of HB, with no effects on concentrations of bupropion or other metabolites. We could account for 50% of the variation in HB concentrations in a model including genotype and sex. CONCLUSION: As HB is active and its steady-state concentrations are more than 10 times higher than bupropion, CYP2B6 variants are likely to affect pharmacological activity. Because of the large individual variation within the genotype group, the use of therapeutic drug monitoring for dose optimization may be necessary.
Authors: Andrew J Johnston; John Ascher; Robert Leadbetter; Virginia D Schmith; Dipak K Patel; Michael Durcan; Beth Bentley Journal: Drugs Date: 2002 Impact factor: 9.546
Authors: S R Faucette; R L Hawke; E L Lecluyse; S S Shord; B Yan; R M Laethem; C M Lindley Journal: Drug Metab Dispos Date: 2000-10 Impact factor: 3.922
Authors: Haoming Zhang; Chitra Sridar; Cesar Kenaan; Hemali Amunugama; David P Ballou; Paul F Hollenberg Journal: J Pharmacol Exp Ther Date: 2011-06-09 Impact factor: 4.030
Authors: A Z X Zhu; L S Cox; N Nollen; B Faseru; K S Okuyemi; J S Ahluwalia; N L Benowitz; R F Tyndale Journal: Clin Pharmacol Ther Date: 2012-11-14 Impact factor: 6.875
Authors: Julia Kirchheiner; Christian Klein; Ingolf Meineke; Johanna Sasse; Ulrich M Zanger; Thomas E Mürdter; Ivar Roots; Jürgen Brockmöller Journal: Pharmacogenetics Date: 2003-10
Authors: Leah M Hesse; Ping He; Soundararajan Krishnaswamy; Qin Hao; Kirk Hogan; Lisa L von Moltke; David J Greenblatt; Michael H Court Journal: Pharmacogenetics Date: 2004-04
Authors: Vishal Lamba; Jatinder Lamba; Kazuto Yasuda; Stephen Strom; Julio Davila; Michael L Hancock; James D Fackenthal; Peter K Rogan; Barbara Ring; Steven A Wrighton; Erin G Schuetz Journal: J Pharmacol Exp Ther Date: 2003-10-09 Impact factor: 4.030
Authors: Naji C Salloum; Erica L F Buchalter; Swati Chanani; Gemma Espejo; Mahjabeen S Ismail; Randy O Laine; Maysaa Nageeb; A Benjamin Srivastava; Nicholas Trapp; Ludwig Trillo; Erica Vance; Michael Wenzinger; Sarah M Hartz; Sean P David; Li-Shiun Chen Journal: Pharmacogenomics Date: 2018-06-19 Impact factor: 2.533
Authors: Zeruesenay Desta; Ingrid F Metzger; Nancy Thong; Jessica B L Lu; John T Callaghan; Todd C Skaar; David A Flockhart; Raymond E Galinsky Journal: Antimicrob Agents Chemother Date: 2016-10-21 Impact factor: 5.191
Authors: Andy Z X Zhu; Qian Zhou; Lisa Sanderson Cox; Jasjit S Ahluwalia; Neal L Benowitz; Rachel F Tyndale Journal: Drug Metab Dispos Date: 2014-09-03 Impact factor: 3.922
Authors: Aaron M Teitelbaum; Alicia M Flaker; Evan D Kharasch Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2016-02-27 Impact factor: 3.205
Authors: Valentina M Fokina; Meixiang Xu; Erik Rytting; Sherif Z Abdel-Rahman; Holly West; Cheryl Oncken; Shannon M Clark; Mahmoud S Ahmed; Gary D V Hankins; Tatiana N Nanovskaya Journal: Drug Metab Dispos Date: 2016-08-15 Impact factor: 3.922
Authors: Valentina M Fokina; Holly West; Cheryl Oncken; Shannon M Clark; Mahmoud S Ahmed; Gary D V Hankins; Tatiana N Nanovskaya Journal: Am J Obstet Gynecol Date: 2016-05-12 Impact factor: 8.661