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Organic Cation Transporters in Drug Interactions with Methamphetamine and Metabolites
Author(s) -
Wagner David James,
Wang Joanne
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.935.6
Subject(s) - methamphetamine , meth , pharmacology , drug , metabolite , organic cation transport proteins , chemistry , transporter , amphetamine , potency , medicine , biochemistry , in vitro , dopamine , monomer , organic chemistry , acrylate , gene , polymer
Methamphetamine (Meth) is the second most commonly abused illicit drug with marijuana being the first. High levels of Meth abuse are reported in individuals receiving treatment for HIV and hepatitis who may be receiving multiple drugs for treatment. Organic cation transporters (OCTs) and multidrug and toxin extrusion transporters (MATEs) are known to be involved in tissue distribution and elimination of a number of these antiretrovirals including lamivudine and zalcitabine. Meth and its main metabolites (amphetamine and p‐hydroxyMeth) are organic cations but their potential effects and drug interaction potential with the OCTs and MATEs are poorly understood. The goal of this study is to determine if Meth and metabolites inhibit renal and hepatic OCTs and MATEs, which may lead to clinically significant drug‐drug interactions with antiretroviral drugs in Meth users. The inhibitory effects of Meth and metabolites are determined using uptake assays in cell lines stably expressing human OCT and MATE transporters and the drug interaction potential is assessed by comparing IC 50 values with reported Meth/metabolite concentrations in drug abusers. Meth inhibited hOCT1, hOCT2, hOCT3, hMATE1, and hMATE2k at clinically relevant drug concentrations with the greatest potencies against hOCT1 (IC 50 = 21 ± 8.8 μM) and hOCT2 (IC 50 = 17 ± 6.8 μM). Amphetamine showed a similar inhibition potency and pattern towards these transporters. p‐hydroxyMeth is a more potent inhibitor of hOCT3, exhibiting approximately 8‐fold greater potency than Meth but was approximately 5‐fold less potent toward hOCT2. Based on the reported blood concentrations of Meth and metabolites in illicit users and the FDA guidance on transporter‐mediated DDIs, our studies suggest potential in vivo drug interactions of Meth with drug substrates of the OCTs and MATEs. This information can be considered when prescribing medications to suspected or known abusers of methamphetamine to mitigate the risk of increased toxicity or reduced therapeutic efficacy. Support or Funding Information This study was supported by NIH grants P01DA032507 and T32GM07750.