The Effect of Dicloxacillin Administration on Pharmacokinetics of Narrow Therapeutic Window Drugs: Phenytoin and Warfarin

Dicloxacillin is a penicillinase-resistant beta-lactam antibiotic and potent activator of the Pregnane X receptor (PXR), known to induce CYP2C9, CYP2C19, and CYP3A4 activity. Clinical data suggest it reduces anticoagulation in warfarin-treated patients and increases the risk of thromboembolic events. This open-label, sequential drug-drug interaction study quantitatively evaluated the effect of dicloxacillin on the pharmacokinetics of warfarin and phenytoin, two prototype CYP2C9 substrates with narrow therapeutic indices, and possible impact of CYP2C9 polymorphisms on the extent of this interaction. Twenty-eight healthy non-smoker subjects, 15 carriers of CYP2C9*1/*1, and 13 carriers of a single CYP2C9*2 or CYP2C9*3 allele, received single doses of warfarin (20 mg) and 1 week later, phenytoin (300 mg) before and during a 21-day course of dicloxacillin 500 mg four times daily. Plasma concentration of warfarin enantiomers and phenytoin and urine concentration of p-HPPH were measured using validated HPLC methods. Warfarin pharmacodynamics was monitored via serial INR measurements for up to 120 hours. Dicloxacillin increased oral clearance of (S)-warfarin and (R)-warfarin by 53.2% and 63.2%, respectively (P < 0.001). The area under the INR-time curve decreased by 15.5% (P < 0.001). Phenytoin oral clearance and p-HPPH formation clearance increased by 42.4% and 40.5%, respectively (P < 0.001). CYP2C9 induction was significantly greater in carriers of CYP2C9*1/*1 genotype and INR reduction was more pronounced among VKORC1 AA haplotype carriers. Dicloxacillin substantially induces the metabolism of warfarin and phenytoin. Whenever dicloxacillin is initiated, the dose of CYP2C9 substrates characterized by a narrow therapeutic window should be increased and drug levels and/or pharmacodynamic response should be closely monitored.