Although the interaction between selective serotonin reuptake inhibitors (SSRIs) and other drugs is important in the treatment of depression, there have been few studies of SSRIs concerning transporter-mediated interactions in humans. The objective of this study was to evaluate the in vivo effects of commonly used SSRIs on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate.Twelve healthy volunteers (3 females and 9 males) were enrolled in this study. Each subject received a 60-mg dose of fexofenadine orally at baseline. Afterward, they were randomly assigned to receive 3 treatments with a 60-mg dose of fexofenadine after a 7-day treatment with fluvoxamine (50 mg/d), paroxetine (20 mg/d), or sertraline (50 mg/d), with 2-week intervals between the agents.Fluvoxamine pretreatment significantly increased the maximum plasma concentration, the area under the concentration time curves, and the 24-hour urinary fexofenadine excretion by 66% (P = 0.004), 78% (P = 0.029), and 78% (P < 0.001), respectively, without prolonging its elimination half-life. Paroxetine extended the elimination half-life of fexofenadine by 45% (P = 0.042), and it increased the 24-hour urinary fexofenadine excretion by 55% (P = 0.002). Sertraline did not alter any of the pharmacokinetic parameters of fexofenadine.This is the first report of the different effects of 3 commonly used SSRIs on fexofenadine pharmacokinetics in humans. Our 7-day, repeated-dose clinical study in healthy volunteers indicates that fluvoxamine and paroxetine, but not sertraline, may impact the patient exposure to fexofenadine, which is likely the result of P-glycoprotein inhibition in the small intestine and/or the liver.