RT Journal Article SR Electronic T1 Disposition of Methamphetamine and Major Metabolites in Mice: Role of Organic Cation Transporter 3 (Oct3) in Tissue Selective Accumulation of para-hydroxymethamphetamine JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.118.082131 DO 10.1124/dmd.118.082131 A1 David J Wagner A1 Laura M Shireman A1 Sojung Ahn A1 Danny D. Shen A1 Joanne Wang YR 2018 UL http://dmd.aspetjournals.org/content/early/2018/06/18/dmd.118.082131.abstract AB Methamphetamine is one of the most widely abused illicit drugs. While human intoxication and multiple tissue toxicities frequently occur in abusers, little is known about the distribution of methamphetamine or its primary metabolites, amphetamine and para-hydroxymethamphetamine (p-OHMA), to their sites of toxicity. This study determined the pharmacokinetics, tissue exposure, and partition ratios of methamphetamine and major metabolites in various mouse tissues and investigated the impact of organic cation transporter 3 (Oct3) following intravenous injection of methamphetamine to male Oct3+/+ and Oct3-/- mice. Methamphetamine, amphetamine and p-OHMA were readily detectable in plasma with Oct3+/+ and Oct3-/- mice displaying similar plasma pharmacokinetic profiles for all three analytes. In addition to kidney and liver, salivary glands highly accumulated methamphetamine, amphetamine and p-OHMA with total exposure 3.3 to 9.4-fold higher than plasma AUC. Consistent with being an Oct3 substrate, p-OHMA AUC in salivary glands is reduced by 50% in Oct3-/- mice. p-OHMA AUC in skeletal muscle is also significantly reduced in Oct3-/- mice. Our data identified salivary glands as a novel site of high accumulation of methamphetamine and metabolites, which may underlie methamphetamine toxicity in this tissue. Furthermore, our study identified Oct3 as an important determinant of tissue uptake and exposure to p-OHMA in salivary glands and skeletal muscle. Our findings suggest that local tissue accumulation of methamphetamine and/or its metabolites may play a role in several of the reported peripheral toxicities of methamphetamine and Oct3 can significantly impact tissue exposure to its substrates without affecting systemic elimination.