Renal interaction between itraconazole and cimetidine.
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.
Renal Clinical Pharmacology Laboratory, School of Pharmacy, and the Department of Medicine, Division of Nephrology, School of Medicine, University of Maryland, Baltimore 21201, USA.
Chetan S
CS
Karyekar
Natalie D
ND
Eddington
Andrew
A
Briglia
Paul O
PO
Gubbins
Thomas C
TC
Dowling
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002927:Cimetidine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004347:Drug Interactions; D005260:Female; D005919:Glomerular Filtration Rate; D006207:Half-Life; D006635:Histamine H2 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007483:Iothalamic Acid; D017964:Itraconazole / Q000494:pharmacology*; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D008297:Male
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000897:Anti-Ulcer Agents; D000935:Antifungal Agents; D006635:Histamine H2 Antagonists; D007483:Iothalamic Acid; D017964:Itraconazole; D002927:Cimetidine