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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.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2008 Apr; Vol. 83 (4), pp. 567-76. Date of Electronic Publication: 2007 Oct 31. - Publication Year :
- 2008
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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.
- Subjects :
- Adult
Benzazepines blood
Benzazepines pharmacology
Benzazepines urine
Chromatography, High Pressure Liquid
Cimetidine pharmacology
Embryo, Mammalian
Enzyme Inhibitors pharmacology
Female
Humans
Kidney cytology
Male
Middle Aged
Organic Cation Transporter 1 antagonists & inhibitors
Organic Cation Transporter 2
Quinoxalines blood
Quinoxalines pharmacology
Quinoxalines urine
Receptors, Nicotinic drug effects
Tandem Mass Spectrometry
Varenicline
Benzazepines pharmacokinetics
Benzazepines therapeutic use
Organic Cation Transport Proteins antagonists & inhibitors
Quinoxalines pharmacokinetics
Quinoxalines therapeutic use
Smoking metabolism
Smoking therapy
Smoking Cessation methods
Subjects
Details
- Language :
- English
- ISSN :
- 1532-6535
- Volume :
- 83
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 17971819
- Full Text :
- https://doi.org/10.1038/sj.clpt.6100405