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.
Karyekar
Chetan S
CS
Renal Clinical Pharmacology Laboratory, School of Pharmacy, and the Department of Medicine, Division of Nephrology, School of Medicine, University of Maryland, Baltimore 21201, USA.
Eddington
Natalie D
ND
Briglia
Andrew
A
Gubbins
Paul O
PO
Dowling
Thomas C
TC
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