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

Dicloxacillin, a PXR activator, induces CYP2C9, CYP2C19 and CYP3A4 activity and accelerates warfarin and phenytoin metabolism, producing drug-induced phenoconversion.

Dicloxacillin, a penicillinase-resistant beta-lactam and potent PXR activator, induces CYP2C9, CYP2C19 and CYP3A4 activity, and clinical data suggest it reduces anticoagulation and increases thromboembolic risk in warfarin-treated patients. This open-label, sequential drug-drug interaction study quantified its effect in 28 healthy non-smoking subjects, 15 with the CYP2C9 1/1 genotype and 13 carrying a single CYP2C9 2 or 3 allele, who received single doses of warfarin (20 mg) and, one week later, phenytoin (300 mg), before and during a 21-day course of dicloxacillin 500 mg four times daily. Dicloxacillin increased oral clearance of (S)-warfarin and (R)-warfarin by 53.2 % and 63.2 % respectively (P < 0.001) and decreased the area under the INR-time curve by 15.5 % (P < 0.001), while phenytoin oral clearance and p-HPPH formation clearance increased by 42.4 % and 40.5 % (P < 0.001). Induction was significantly greater in CYP2C9 1/1 subjects and the INR reduction more pronounced among VKORC1 AA haplotype carriers. The authors recommend that when dicloxacillin is started, the dose of narrow therapeutic window CYP2C9 substrates be increased and drug levels and pharmacodynamic response closely monitored.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is a case of reverse phenoconversion: the antibiotic turns a normal metabolizer into an accelerated one, and the apparently most favourable genotype becomes the most exposed to loss of anticoagulation. Scope is limited by the design — 28 healthy volunteers, single doses, no clinical events — so we have an induction magnitude but no quantified adjustment rule: increase the dose and monitor is not a posology. The operational message is therefore to reinforce INR monitoring during the course and after it stops, since resolution of induction carries just as much risk of overdose.

Analysis by Dr Thibaut Benquey