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Renal interaction between itraconazole and cimetidine.
Chetan S Karyekar1, Natalie D Eddington, Andrew Briglia
1Renal Clinical Pharmacology Laboratory, School of Pharmacy, and the Department of Medicine, Division of Nephrology, School of Medicine, University of Maryland, Baltimore 21201, USA.
Journal of Clinical Pharmacology
|August 3, 2004
Summary
Itraconazole, a P-glycoprotein inhibitor, significantly reduced cimetidine renal tubular secretion and clearance in healthy volunteers. This drug interaction increased cimetidine
Area of Science:
- Pharmacology
- Nephrology
- Drug Metabolism
Background:
- Renal drug interactions can occur via competitive inhibition of renal tubular secretion.
- P-glycoprotein (P-gp) is a key transporter involved in the renal excretion of many drugs.
Purpose of the Study:
- To investigate the impact of itraconazole, a P-gp inhibitor, on the renal tubular secretion of cimetidine.
- To assess changes in cimetidine pharmacokinetics and renal clearance in healthy volunteers.
Main Methods:
- Healthy volunteers received intravenous cimetidine alone and after 3 days of oral itraconazole (400 mg/day).
- Glomerular filtration rate (GFR) was measured using iothalamate clearance.
- Plasma and urine concentrations of iothalamate, cimetidine, and itraconazole were quantified using HPLC/UV.
- Renal tubular secretion (CLsec) of cimetidine was calculated.
Main Results:
- Coadministration with itraconazole increased cimetidine area under the curve (AUC) by 25% (p < 0.01).
- GFR and volume of distribution (Vd) remained unchanged.
- Significant reductions in total clearance (CL(T)) and renal tubular secretion (CLsec) of cimetidine were observed (p < 0.001 and p = 0.001, respectively).
Conclusions:
- Itraconazole inhibits P-gp-mediated renal tubular secretion of cimetidine.
- This inhibition leads to increased systemic exposure of cimetidine.
- Further studies on P-gp-modulating drugs are warranted to understand potential drug interactions.