Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P‐glycoprotein

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Abstract
Aims: Fexofenadine is a substrate of several drug transporters including P‐glycoprotein. Our objective was to evaluate the possible effects of two P‐glycoprotein inhibitors, itraconazole and diltiazem, on the pharmacokinetics of fexofenadine, a putative probe of P‐glycoprotein activityin vivo, and compare the inhibitory effect between the two in healthy volunteers.Methods: In a randomized three‐phase crossover study, eight healthy volunteers were given oral doses of 100 mg itraconazole twice daily, 100 mg diltiazem twice daily or a placebo capsule twice daily (control) for 5 days. On the morning of day 5 each subject was given 120 mg fexofenadine, and plasma concentrations and urinary excretion of fexofenadine were measured up to 48 h after dosing.Results: Itraconazole pretreatment significantly increased mean (± SD) peak plasma concentration (Cmax) of fexofenadine from 699 (± 366) ng ml−1to 1346 (± 561) ng ml−1(95% CI of differences 253, 1040;P < 0.005) and the area under the plasma concentration‐time curve [AUC(0,∞)] from 4133 (± 1776) ng ml−1 h to 11287 (± 4552) ng ml−1 h (95% CI 3731, 10575;P < 0.0001). Elimination half‐life and renal clearance in the itraconazole phase were not altered significantly compared with those in the control phase. In contrast, diltiazem pretreatment did not affectCmax(704 ± 316 ng ml−1, 95% CI −145, 155), AUC(0, ∞) (4433 ± 1565 ng ml−1 h, 95% CI −1353, 754), or other pharmacokinetic parameters of fexofenadine.Conclusions: Although some drug transporters other than P‐glycoprotein are thought to play an important role in fexofenadine pharmacokinetics, itraconazole pretreatment increased fexofenadine exposure, probably due to the reduced first‐pass effect by inhibiting the P‐glycoprotein activity. As diltiazem pretreatment did not alter fexofenadine pharmacokinetics, therapeutic doses of diltiazem are unlikely to affect the P‐glycoprotein activityin vivo.