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

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 activity in 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−1 to 1346 (± 561) ng ml−1 (95% CI of differences 253, 1040; P