Methadone is used as a maintenance treatment for opiate addiction and is the standard of care in the management of the pregnant opiate-addicted woman. Maternal methadone dose at delivery and the severity of neonatal withdrawal are closely related. Thus, methadone dose is a critical factor determining both maternal health and birth outcome. Most dosage regimens for methadone are empirical, titrating dose against withdrawal symptoms and, where appropriate, on the history of opiate use. Despite the use of methadone for nearly 50 years, details of its pharmacokinetics are surprisingly incomplete. A linear relationship has been reported between methadone dose and drug concentration in plasma but drug dose explains less than 50 percent of the variability. Methadone is marketed as a mixture (50:50) of 2 enantiomers called (R)-methadone and (S)-methadone, but (R)methadone accounts for nearly all of the opioid effects of the racemic dose. The disposition of methadone appears to be stereoselective and under genetic and environmental control. The pharmacogenetic contribution to methadone's disposition has received little study. Accordingly, a three-year dual-site, collaborative ROl study is proposed to define the major pharmacogenetic variables that influence the disposition of methadone in women. The major determinants to be studied include 1) gender, 2) ethnic origin (Africian-American vs. Caucasian background), 3) enantioselective metabolism; 4) plasma protein binding of methadone's enantiomers, 5) genetically determined phenotype of alpha1-acid glycoprotein (AGP), 5) the cortisol ratio as a surrogate marker of cytochrome P-450 (CYP) 3A4 activity, and 6) genotype of CYP2D6. A rigorous pharmacokinetic study of methadone disposition will be completed in healthy volunteer women and the results compared to healthy men. Correlations will be sought between the pharmacokinetics of methadone's enantiomers and effect measures shown in our preliminary data to be highly related (pupillary constriction, oral temperature, blood glucose concentration). Demographic and pharmacokinetic data will be obtained from 600 women (240 in Charleston and 360 in Cincinnati) receiving methadone maintenance. A population pharmacokinetic model will be constructed and tested to predict plasma concentrations of active (R)-methadone before and during pregnancy. The goals of this research are to describe the major pharmacogenetic factors which influence methadone concentration in women, and through pharmacokinetic analyses, to form a clearer understanding of the dose-concentration-effect relationship of methadone in a special population at risk, the pregnant opiate-addicted woman. This study will form the basis for subsequent studies which should provide a more rational basis for dosing of methadone in pregnant addicts.
