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Phenytoin metabolic ratio (PMR) correlates with formation clearance of (S)‐7‐OH‐warfarin
Author(s) -
Adar L.,
Bialer M.,
Blotnick S.,
Caraco Y.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.122
Subject(s) - cyp2c9 , warfarin , phenytoin , metabolite , urine , chemistry , pharmacology , medicine , pharmacokinetics , urinary system , metabolism , atrial fibrillation , cytochrome p450 , psychiatry , epilepsy
Aim To 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. Methods CYP2C9 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. Results A 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