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Pharmacogenetics of Nicotine Metabolism in Twins: Methods and Procedures

Published online by Cambridge University Press:  21 February 2012

Gary E. Swan*
Affiliation:
Center for Health Sciences, SRI International, California, United States of America. gary.swan@sri.com
Neal L. Benowitz
Affiliation:
Division of Clinical Pharmacology, Departments of Medicine and Biopharmaceutical Sciences, University of California, San Francisco, United States of America.
Peyton Jacob III
Affiliation:
Division of Clinical Pharmacology, Departments of Medicine and Biopharmaceutical Sciences, University of California, San Francisco, United States of America.
Christina N. Lessov
Affiliation:
Center for Health Sciences, SRI International, California, United States of America.
Rachel F. Tyndale
Affiliation:
Department of Pharmacology, University of Toronto, Canada.
Kirk Wilhelmsen
Affiliation:
Department of Genetics, University of North Carolina, United States of America.
Ruth E. Krasnow
Affiliation:
Center for Health Sciences, SRI International, California, United States of America.
Mary R. McElroy
Affiliation:
Center for Health Sciences, SRI International, California, United States of America.
Sharyn E. Moore
Affiliation:
Center for Health Sciences, SRI International, California, United States of America.
Michelle Wambach
Affiliation:
Center for Health Sciences, SRI International, California, United States of America.
*Corresponding
*Address for correspondence: Gary E. Swan, Center for Health Sciences, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.

Abstract

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This article describes a pharmacogenetic investigation of nicotine metabolism in twins. One hundred and thirty-nine twin pairs (110 monozygotic and 29 dizygotic) were recruited and assessed for smoking status, zygosity, and health conditions known or suspected to affect drug metabolism. Participants underwent a 30-minute infusion of stable isotope-labeled nicotine and its major metabolite, cotinine, followed by an 8-hour in-hospital stay. Blood and urine samples were taken at regular intervals for analysis of nicotine, cotinine, and metabolites by gas chromatography–mass spectrometry or liquid chromatography–mass spectrometry and subsequent characterization of pharmacokinetic phenotypes. DNA was genotyped to confirm zygosity and for variation in the primary gene involved in nicotine metabolism, CYP2A6. Univariate and multivariate biometric analyses planned for the future will determine genetic and environmental influences on each pharmacokinetic measure individually and in combination with each other, and in the presence and absence of covariates, including measured genotype. When the analyses are completed, this study will result in a more complete characterization of the impact of genetic and environmental influences on nicotine and cotinine metabolic pathways than has heretofore been reported. The approach taken, with its use of a quantitative model of nicotine metabolism, highly refined metabolic phenotypes, measured genotype, and advanced tools for biometric genetic analysis, provides a model for the use of twins in next-generation studies of complex drug-metabolism phenotypes.

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