The Role of Organic Cation Transporters in the Disposition, Drug-Drug Interactions, and Tissue Toxicity of Amphetamines

Abstract

This dissertation research aims to elucidate the roles of organic cation transporters in the disposition, drug-drug interactions, and toxicity of methamphetamine. Work conducted in this dissertation research has elucidated the molecular mechanisms involved in transport and disposition of methamphetamine and its metabolites and provided novel insights into the in vivo significance of OCTs in the disposition, potential drug-drug interactions, and toxicities of this widely used drug of abuse. In Chapter 2, I showed methamphetamine and its metabolites interact with hOCT1-3 and hMATE1/2-K at clinically relevant concentrations. I further demonstrated that methamphetamine and amphetamine are substrates of hOCT2, hMATE1, and hMATE2-K, suggesting that the hOCT2/hMATEs pathway is involved in renal secretion of methamphetamine and its metabolites. Following the identification of complex transport kinetics in Chapter 2, Chapter 3 demonstrated that the apparent mechanism of inhibition depends on the substrate transport kinetics and sidedness of the inhibitory interaction. These findings suggest some hOCT2 substrates have spatially distinct binding sites within the binding region and may likely be transported simultaneously. Chapter 4 determined the pharmacokinetics, tissue exposure, and partition ratios of methamphetamine and major metabolites in various mouse tissues and investigated the impact of Oct3 on the tissue-specific accumulation of p-OHMA. The data demonstrated that salivary glands are a novel site of exceedingly high accumulation of methamphetamine, amphetamine, and p-OHMA. Furthermore, Chapter 4 identified Oct3 as an important determinant of tissue uptake of and exposure to p-OHMA in salivary glands and skeletal muscle. These findings suggest that local tissue accumulation of methamphetamine and/or its metabolites may play a direct role in several of the reported peripheral toxicities of methamphetamine and Oct3 can significantly impact tissue exposure to drugs and drug metabolites independently from their systemic exposure. This dissertation research has contributed greatly to our understanding of transporter mediated disposition, drug-drug interactions, and toxicity of the drugs of abuse methamphetamine and β-carbolines. Taken together, this research provides useful information that may be considered when prescribing medications to methamphetamine users to mitigate the risk of DDIs that may potentially compromise therapeutic efficacy and drug safety.