Interaction and Transport of Methamphetamine and its Primary Metabolites by Organic Cation and Multidrug and Toxin Extrusion Transporters

Abstract

Methamphetamine is one of the most abused illicit drugs with roughly 1.2 million users in the United States alone. A large portion of methamphetamine and its metabolites is eliminated by the kidney with renal clearance larger than glomerular filtration clearance. Yet the mechanism of active renal secretion is poorly understood. The goals of this study were to characterize the interaction of methamphetamine and its major metabolites with organic cation transporters (OCTs) and multidrug and toxin extrusion (MATE) transporters and to identify the major transporters involved in the disposition of methamphetamine and its major metabolites, amphetamine and -hydroxymethamphetamine (-OHMA). We used cell lines stably expressing relevant transporters to show that methamphetamine and its metabolites inhibit human OCTs 1-3 (hOCT1-3) and hMATE1/2-K with the greatest potencies against hOCT1 and hOCT2. Methamphetamine and amphetamine are substrates of hOCT2, hMATE1, and hMATE2-K, but not hOCT1 and hOCT3. -OHMA is transported by hOCT1-3 and hMATE1, but not hMATE2-K. In contrast, organic anion transporters 1 and 3 do not interact with or transport these compounds. Methamphetamine and its metabolites exhibited complex interactions with hOCT1 and hOCT2, suggesting the existence of multiple binding sites. Our studies suggest the involvement of the renal OCT2/MATE pathway in tubular secretion of methamphetamine and its major metabolites and the potential of drug-drug interactions with substrates or inhibitors of the OCTs. This information may be considered when prescribing medications to suspected or known abusers of methamphetamine to mitigate the risk of increased toxicity or reduced therapeutic efficacy.

Structural properties for selective and efficient l-type amino acid transporter 1 (LAT1) mediated cellular uptake

“…This could occur after the binding affinity to the primary active site has been enhanced by binding of substrate to an allosteric site (Ueng, et al 1997). This phenomenon has earlier been observed in drugmetabolizing enzymes (Atkins 2005;Galetin, et al 2003) and drug transporters (Shapiro and Ling 1997;Shapiro, et al 1999;Wagner, et al 2017;Zhou, et al 2007), particularly in those exhibiting broad substrate specificities (e.g., cytochrome P450 3A4 (CYP3A), multidrug resistance protein 1 (MDR1) and proton-stimulated organic cation transporter (plasma membrane monoamine tranporter (PMAT)) in a substrate-dependent manner. In previous in vitro studies in Madin-Darby canine kidney (MDCK) cells stably expressing PMAT, utilized for investigating the cellular uptake of serotonin, a typical linear kinetic plot was seen (Engel, et al 2004).…”

Mechanistic PBPK Modeling of Urine pH Effect on Renal and Systemic Disposition of Methamphetamine and Amphetamine

“…Three 200 µL aliquots were centrifuged in 435,000 g for 90 min at 37 °C and another three 200 µL aliquots were incubated at 37 °C for 90 min. The supernatant (50 µL) from the ultracentrifugation and the incubated samples (50 µL) were then quenched with 250 µL of 3:1 (v/v) acetonitrile:methanol containing 100 nM methamphetamine-d11 and amphetamine-d11 as internal standards and analyzed by LC-MS/MS as previously described (Wagner et al, 2017).…”

Detection, pharmacokinetics, and selected pharmacodynamic effects of methamphetamine following a single transmucosal and intravenous administration to exercised Thoroughbred horses

“…Although a limited number of animals was studied at each dose following transmucosal administration, there was not a significant difference in the terminal half‐life between doses. In other species, methamphetamine is eliminated both by hepatic metabolism and renal tubular secretion . In humans, approximately 37%–54% of methamphetamine is recovered as parent compound in the urine and 4%–7% as amphetamine .…”

“…In other species, methamphetamine is eliminated both by hepatic metabolism and renal tubular secretion. 18 In humans, approximately 37%-54% of methamphetamine is recovered as parent compound in the urine and 4%-7% as amphetamine. 5,6,9 Renal clearance of methamphetamine reportedly far exceeds the glomerular filtration rate 18 suggesting that renal tubular secretion may play a large role in the elimination of methamphetamine in humans.…”

“…18 In humans, approximately 37%-54% of methamphetamine is recovered as parent compound in the urine and 4%-7% as amphetamine. 5,6,9 Renal clearance of methamphetamine reportedly far exceeds the glomerular filtration rate 18 suggesting that renal tubular secretion may play a large role in the elimination of methamphetamine in humans. 11 While the current study was not designed to allow for determination of renal clearance, methamphetamine was the primary compound detected in the urine with very low concentrations of metabolite (amphetamine) recovered.…”