Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ ultraviolet (HPLC/UV) methods. Renal tubular secretion (CLsec) of cimetidine was calculated as the difference between renal clearance (CLr) andGFR (CLioth) ondays 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CLT), volume of distribution (Vd), elimination rate constant (Kel), area under the plasma concentrationtime curve (AUC0-240 min), and average plasma concentration (Cpave) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 μg/mL. The cimetidine AUC0-240 min increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CLT (655 vs. 486 mL/min, p < 0.001) and CLsec (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gpmediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole thatmay alter the renal excretion of coadministered drugs is warranted