title: Evaluation of potential losartan-phenytoin drug interactions in healthy volunteers.
abstract: 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 x h/mL versus 427 +/- 177 ng x 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 x h/mL versus 402 +/- 128 ng x h/mL; P =.008). Coadministration of phenytoin significantly reduced the AUC(0-24) of E3174 by 63% (1254 +/- 256 ng x h/mL versus 466 +/- 174 ng x 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.
authors.affiliation: Division of Pharmacotherapy, School of Pharmacy, University of North Carolina at Chapel Hill 27599, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Fischer
authors.forename: John A
authors.initials: JA
authors.lastname: Pieper
authors.forename: Donald W
authors.initials: DW
authors.lastname: Graff
authors.forename: Jo E
authors.initials: JE
authors.lastname: Rodgers
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Fischer
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Parnell
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Goldstein
authors.forename: Robert
authors.initials: R
authors.lastname: Greenwood
authors.forename: J Herbert
authors.initials: JH
authors.lastname: Patterson
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D019808:Losartan / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D010672:Phenytoin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011446:Prospective Studies; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism
chemical_list: D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D019808:Losartan