Effect of human renal cationic transporter inhibition on the pharmacokinetics of varenicline, a new therapy for smoking cessation: an in vitro-in vivo study.

摘要: 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 transporters demonstrated that high concentrations of varenicline inhibited substrate uptake by hOCT2 (IC50=890 μM), very weak or no measurable interactions the other hOAT1, hOAT3, hOCTN1, hOCTN2. was characterized as a moderate-affinity for (Km=370 μM) hOCT2-mediated cimetidine. Co-administration cimetidine (1,200 mg/day) reduced clearance 12 smokers, resulting 29.0% (90% CI: 21.5%–36.9%) increase systemic exposure. This not considered clinically relevant, it should give rise safety concerns. Consequently, can be reasonably expected inhibitors would cause greater than seen efficient inhibitor cimetidine. Clinical Pharmacology & Therapeutics (2008); 83, 4, 567–576.doi:10.1038/sj.clpt.6100405