Evaluation of potential losartan-phenytoin drug interactions in healthy volunteers

• Published in: Clinical pharmacology and therapeutics 2002-09, Vol.72 (3), p.238-246
• Main Authors: Fischer, Tracy L., Pieper, John A., Graff, Donald W., Rodgers, Jo E., Fischer, Jeffrey D., Parnell, Kimberly J., Goldstein, Joyce A., Greenwood, Robert, Patterson, J. Herbert
• Format: Article
• Language: English
• Subjects: Adult; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Cross-Over Studies; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System - metabolism; Drug Interactions - physiology; Female; Humans; Losartan - adverse effects; Losartan - blood; Losartan - pharmacokinetics; Male; Phenytoin - adverse effects; Phenytoin - blood; Phenytoin - pharmacokinetics; Prospective Studies; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases - metabolism
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1067/mcp.2002.127945

Background Phenytoin, a cytochrome P450 (CYP) 2C9 substrate, has a narrow therapeutic index and nonlinear pharmacokinetics. Therefore there is the potential for significant concentration‐related adverse effects when phenytoin is coadministered with other CYP2C9 substrates. Losartan, an antihypertensive agent, is also a substrate for CYP2C9. Objective Our objective was to assess the effects of losartan on the pharmacokinetics of phenytoin and the effects of phenytoin on the pharmacokinetics of losartan in a healthy population of volunteers. Methods A prospective, randomized, 3‐period crossover study was conducted in 16 healthy volunteers with phenytoin alone, phenytoin in combination with losartan, and losartan alone. Each treatment was given for 10 days with a 3‐week washout period between treatments. On day 10, plasma concentrations of phenytoin and plasma and urine concentrations of losartan and its active carboxylic‐acid metabolite E3174 were measured to determine steady‐state pharmacokinetic parameters. Results Coadministration of losartan had no effect on the pharmacokinetics of phenytoin. Coadministration of phenytoin increased the mean area under the concentration‐time curve from time zero to 24 hours [AUC(0–24)] of losartan by 17% (355 ± 220 ng · h/mL versus 427 ± 177 ng · h/mL; P = .1), but this difference was not statistically significant. In the 14 CYP2C9*1/*1 subjects, the mean AUC(0–24) of losartan was increased by 29% (284 ± 84 ng · h/mL versus 402 ± 128 ng · h/mL; P = .008). Coadministration of phenytoin significantly reduced the AUC(0–24) of E3174 by 63% (1254 ± 256 ng · h/mL versus 466 ± 174 ng · h/mL; P = .0001) and the formation clearance of losartan to E3174 (1.91 ± 0.8 mL/h per kilogram versus 0.62 ± 0.4 mL/h per kilogram; P = .0001). Conclusions Losartan, a CYP2C9 substrate, had no effect on the pharmacokinetics of phenytoin. However, phenytoin inhibited the CYP2C9‐mediated conversion of losartan to E3174. Clinical Pharmacology & Therapeutics (2002) 72, 238–246; doi: 10.1067/mcp.2002.127945