Phenytoin metabolic ratio (PMR) correlates with formation clearance of (S)-7-OH-warfarin (original) (raw)

Clinical Pharmacology & Therapeutics, 2005

Abstract

ABSTRACT AimTo examine the correlation between PMR, a phenotypic marker of CYP2C9, and formation clearance (CLf) of (S)-7-OH-warfarin (S7HW), the CYP2C9 mediated major metabolite of (S)-warfarin, in order to evaluate whether PMR is predictive of warfarin (W) maintenance dose.MethodsCYP2C9 activity was evaluated by way of PMR defined as the ratio of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) content in a 24 hours urine collection to mid-interval plasma phenytoin concentration on 31 hospitalized patients prior to W initiation. Once stable anticoagulation was reached, CLf of S7HW was derived from the ratio of urinary S7HW in a 24 hours collection to mid-interval plasma (S)-W concentration.ResultsA significant correlation was noted between PMR and CLf of S7HW (r=0.66, p=0.01), both of which exhibited marked inter-individual variability (49 and 31.9-fold, respectively). CLf of S7HW was greater in CYP2C9*1 homozygous (n=10,15.2±6.6 ml/min/kg*1000, 95% CI, 10.5 to 19.9) or carriers of one variant allele (n=17, 12.9±6.4 ml/min/kg*1000, 95% CI, 9.6 to 16.2) than in carriers of 2 variant alleles (n=4, 2.50±1.2 ml/min/kg*1000, 95% CI, 0.5 to 4.5, p<0.05).Conclusions These preliminary findings suggest that CYP2C9 activity as evaluated by PMR can be predictive of W oxidation to S7HW.Clinical Pharmacology & Therapeutics (2005) 77, P61-P61; doi: 10.1016/j.clpt.2004.12.122

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