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Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics.
Clin Pharmacol Ther. 2005 Jan; 77(1):17-23.CP

Abstract

OBJECTIVE

Fexofenadine is a substrate of P-glycoprotein and organic anion transporting polypeptides. The aim of this study was to compare the inhibitory effects of different transporting inhibitors on fexofenadine pharmacokinetics.

METHODS

Twelve male volunteers took a single oral 120-mg dose of fexofenadine. Thereafter three 6-day courses of either 240 mg verapamil, an inhibitor of P-glycoprotein, 800 mg cimetidine, an inhibitor of organic cation transporters, or 2000 mg probenecid, an inhibitor of organic anion transporting polypeptides, were administered on a daily basis in a randomized fashion with the same dose of fexofenadine on day 6. Plasma and urine concentrations of fexofenadine were monitored up to 48 hours after dosing.

RESULTS

Verapamil treatment significantly increased the peak plasma concentration by 2.9-fold (95% confidence interval [CI], 2.4- to 4.0-fold) and the area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of fexofenadine by 2.5-fold (95% CI, 2.0- to 3.3-fold). No changes in any plasma pharmacokinetic parameters of fexofenadine were found during cimetidine treatment. AUC(0-infinity) was slightly but significantly increased during probenecid treatment by 1.5-fold (95% CI, 1.1- to 2.4-fold). Renal clearance of fexofenadine was significantly decreased during cimetidine treatment to 61% (95% CI, 50%-98%) and during probenecid treatment to 27% (95% CI, 20%-58%) but not during verapamil treatment.

CONCLUSION

This study suggests that verapamil increases fexofenadine exposure probably because of an increase in bioavailability through P-glycoprotein inhibition and that probenecid slightly increases the area under the plasma concentration-time curve of fexofenadine as a result of a pronounced reduction in renal clearance. However, it may be difficult to explain these interactions by simple inhibitory mechanisms on target transporters.

Authors+Show Affiliations

Department of Clinical Pharmacology, Hirosaki University Schoo of Medicine, Hirosaki 036-8502, Japan. yasufuru@cc.hirosaki-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

15637527

Citation

Yasui-Furukori, Norio, et al. "Different Effects of Three Transporting Inhibitors, Verapamil, Cimetidine, and Probenecid, On Fexofenadine Pharmacokinetics." Clinical Pharmacology and Therapeutics, vol. 77, no. 1, 2005, pp. 17-23.
Yasui-Furukori N, Uno T, Sugawara K, et al. Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics. Clin Pharmacol Ther. 2005;77(1):17-23.
Yasui-Furukori, N., Uno, T., Sugawara, K., & Tateishi, T. (2005). Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics. Clinical Pharmacology and Therapeutics, 77(1), 17-23.
Yasui-Furukori N, et al. Different Effects of Three Transporting Inhibitors, Verapamil, Cimetidine, and Probenecid, On Fexofenadine Pharmacokinetics. Clin Pharmacol Ther. 2005;77(1):17-23. PubMed PMID: 15637527.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics. AU - Yasui-Furukori,Norio, AU - Uno,Tsukasa, AU - Sugawara,Kazunobu, AU - Tateishi,Tomonori, PY - 2005/1/8/pubmed PY - 2005/2/3/medline PY - 2005/1/8/entrez SP - 17 EP - 23 JF - Clinical pharmacology and therapeutics JO - Clin. Pharmacol. Ther. VL - 77 IS - 1 N2 - OBJECTIVE: Fexofenadine is a substrate of P-glycoprotein and organic anion transporting polypeptides. The aim of this study was to compare the inhibitory effects of different transporting inhibitors on fexofenadine pharmacokinetics. METHODS: Twelve male volunteers took a single oral 120-mg dose of fexofenadine. Thereafter three 6-day courses of either 240 mg verapamil, an inhibitor of P-glycoprotein, 800 mg cimetidine, an inhibitor of organic cation transporters, or 2000 mg probenecid, an inhibitor of organic anion transporting polypeptides, were administered on a daily basis in a randomized fashion with the same dose of fexofenadine on day 6. Plasma and urine concentrations of fexofenadine were monitored up to 48 hours after dosing. RESULTS: Verapamil treatment significantly increased the peak plasma concentration by 2.9-fold (95% confidence interval [CI], 2.4- to 4.0-fold) and the area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of fexofenadine by 2.5-fold (95% CI, 2.0- to 3.3-fold). No changes in any plasma pharmacokinetic parameters of fexofenadine were found during cimetidine treatment. AUC(0-infinity) was slightly but significantly increased during probenecid treatment by 1.5-fold (95% CI, 1.1- to 2.4-fold). Renal clearance of fexofenadine was significantly decreased during cimetidine treatment to 61% (95% CI, 50%-98%) and during probenecid treatment to 27% (95% CI, 20%-58%) but not during verapamil treatment. CONCLUSION: This study suggests that verapamil increases fexofenadine exposure probably because of an increase in bioavailability through P-glycoprotein inhibition and that probenecid slightly increases the area under the plasma concentration-time curve of fexofenadine as a result of a pronounced reduction in renal clearance. However, it may be difficult to explain these interactions by simple inhibitory mechanisms on target transporters. SN - 0009-9236 UR - https://www.unboundmedicine.com/medline/citation/15637527/Different_effects_of_three_transporting_inhibitors_verapamil_cimetidine_and_probenecid_on_fexofenadine_pharmacokinetics_ L2 - https://doi.org/10.1016/j.clpt.2004.08.026 DB - PRIME DP - Unbound Medicine ER -