title: Effect of human renal cationic transporter inhibition on the pharmacokinetics of varenicline, a new therapy for smoking cessation: an in vitro-in vivo study.
abstract: 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 microM), 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 microM) 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.
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, Drug Metabolism, Pfizer Global Research & Development, Groton, Connecticut, USA.
authors.forename: B
authors.initials: B
authors.lastname: Feng
authors.forename: R S
authors.initials: RS
authors.lastname: Obach
authors.forename: A H
authors.initials: AH
authors.lastname: Burstein
authors.forename: D J
authors.initials: DJ
authors.lastname: Clark
authors.forename: S M
authors.initials: SM
authors.lastname: de Morais
authors.forename: H M
authors.initials: HM
authors.lastname: Faessel
mesh_terms: D000328:Adult; D001552:Benzazepines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D002927:Cimetidine / Q000494:pharmacology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007668:Kidney / Q000166:cytology; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D027702:Organic Cation Transporter 1 / Q000037:antagonists & inhibitors; D000075102:Organic Cation Transporter 2; D011810:Quinoxalines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use* / Q000652:urine; D011978:Receptors, Nicotinic / Q000187:drug effects; D012907:Smoking / Q000378:metabolism* / Q000628:therapy*; D016540:Smoking Cessation / Q000379:methods*; D053719:Tandem Mass Spectrometry; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D004791:Enzyme Inhibitors; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C491013:SLC22A2 protein, human; D002927:Cimetidine; D000068580:Varenicline