1. ¹Department of Pharmacokinetics, Pharmacodynamics, Drug Metabolism, Pfizer Global Research & Development, Groton, Connecticut, USA
2. ²Department of Clinical Research Operations, Pfizer Global Research & Development, Groton, Connecticut, USA
3. ³Department of Neurosciences, Pfizer Global Research & Development, Groton, Connecticut, USA
4. ⁴Department of Clinical Pharmacology, Pfizer Global Research & Development, Groton, Connecticut, USA

Correspondence: HM Faessel, (helene.m.faessel@pfizer.com)

Received 5 April 2007; Accepted 31 August 2007; Published online 31 October 2007.

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 (IC₅₀=890 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 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.