Disposition of Methamphetamine and Major Metabolites in Mice: Role of Organic Cation Transporter 3 in Tissue-Selective Accumulation of Para-Hydroxymethamphetamine

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Abstract
Methamphetamine is one of the most widely abused illicit drugs. Although 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 i.v. 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 area under the concentration–time curve (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.

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