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Effect of Human Renal Cationic Transporter Inhibition on the Pharmacokinetics of Varenicline, a New Therapy for Smoking Cessation: An In Vitro – In Vivo Study
Author(s) -
Feng B,
Obach RS,
Burstein AH,
Clark DJ,
Morais SM,
Faessel HM
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100405
Subject(s) - varenicline , pharmacology , cimetidine , transporter , pharmacokinetics , in vivo , chemistry , kidney , organic cation transport proteins , medicine , biochemistry , biology , nicotine , microbiology and biotechnology , gene
Varenicline is predominantly eliminated unchanged in urine, and active tubular secretion partially contributes to its renal elimination. Transporter inhibition assays using human embryonic kidney 293 cells transfected with human renal transporters demonstrated that high concentrations of varenicline inhibited substrate uptake by hOCT2 (IC 50 =890 μ M ), with very weak or no measurable interactions with the other transporters hOAT1, hOAT3, hOCTN1, and hOCTN2. Varenicline was characterized as a moderate‐affinity substrate for hOCT2 ( K m =370 μ M ) and its hOCT2‐mediated uptake was partially inhibited by cimetidine. Co‐administration of cimetidine (1,200 mg/day) reduced the renal clearance of varenicline in 12 smokers, resulting in a 29.0% (90% CI: 21.5%–36.9%) increase in systemic exposure. This increase is not considered clinically relevant, as it should not give rise to safety concerns. Consequently, it can be reasonably expected that other inhibitors of hOCT2 would not cause greater renal interactions with varenicline than that seen with the efficient hOCT2 inhibitor cimetidine. Clinical Pharmacology & Therapeutics (2008); 83 , 4, 567–576.doi: 10.1038/sj.clpt.6100405