Renal interaction between itraconazole and cimetidine

J Clin Pharmacol. 2004 Aug;44(8):919-27. doi: 10.1177/0091270004266783.


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 (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (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-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Administration, Oral
  • Adult
  • Anti-Ulcer Agents / pharmacokinetics*
  • Antifungal Agents / pharmacology*
  • Area Under Curve
  • Cimetidine / blood
  • Cimetidine / pharmacokinetics*
  • Cimetidine / urine
  • Drug Interactions
  • Female
  • Glomerular Filtration Rate
  • Half-Life
  • Histamine H2 Antagonists / pharmacokinetics*
  • Humans
  • Iothalamic Acid
  • Itraconazole / pharmacology*
  • Kidney Tubules / drug effects*
  • Kidney Tubules / metabolism
  • Male


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Ulcer Agents
  • Antifungal Agents
  • Histamine H2 Antagonists
  • Iothalamic Acid
  • Itraconazole
  • Cimetidine