Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics.
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.


CONCLUSIONS
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.
Yasui-Furukori
Norio
N
Department of Clinical Pharmacology, Hirosaki University Schoo of Medicine, Hirosaki 036-8502, Japan. yasufuru@cc.hirosaki-u.ac.jp
Uno
Tsukasa
T
Sugawara
Kazunobu
K
Tateishi
Tomonori
T
D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002927:Cimetidine / Q000494:pharmacology*; D004347:Drug Interactions; D006207:Half-Life; D006634:Histamine H1 Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011339:Probenecid / Q000494:pharmacology*; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014528:Uricosuric Agents / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D014528:Uricosuric Agents; D016593:Terfenadine; D002927:Cimetidine; D014700:Verapamil; C093230:fexofenadine; D011339:Probenecid