PII-086 - QUANTITATIVE EFFECT OF CYP2C9 INDUCTION BY DICLOXACILLIN ON THE NARROW THERAPEUTIC DRUGS: PHENYTOIN AND WARFARIN.

C. Shaul¹, W. Mujahed², I. Ibrahem², M. Wanounou², Y. Caraco²; ¹Shaary-Zedek Medical Center, Jerusalem, Israel, ²Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Background: Dicloxacillin has an induction effect on CYP3A4, CYP2C9, and CYP2C19. Intake of dicloxacillin by patients on chronic warfarin therapy is associated with thromboembolic events.

Aim: Qualitative evaluation of the induction effect of dicloxacillin on the pharmacokinetics of phenytoin and warfarin, CYP2C9 substrates characterized as narrow therapeutic drugs.

Methods: The study population consisted of 30 healthy subjects, 15 carriers of CYP2C9*1/*1 and 15 carriers of a single CYP2C9*2 or CYP2C9*3 variant allele. Urine was collected, and periodic blood samples were obtained for 96-120 hours following the administration of a single warfarin (20 mg) and phenytoin (300 mg) dose administered on two separate occasions one week apart. The same procedure was performed following 10 days treatment with dicloxacillin 500 mg QID. (S/R)-warfarin oral clearance (S/RWOCL), INR values, phenytoin oral clearance, and p-HPPH formation clearance were compared before and after dicloxacillin exposure.

Results: Following dicloxacillin administration, SWOCL and RWOCL were increased from 0.19±0.09 to 0.27±0.08 L/h and from 0.13±0.04 to 0.19±0.05 L/h, respectively (p < 0.005). The area under the INR 120h time curve was reduced from 185±36 to 154±20 (p < 0.001). Phenytoin oral clearance and p-HPPH formation clearance were similarly increased from 1.8±0.7 to 2.6±0.9 L/h and from 0.5±0.2 to 0.7±0.2 L/h, respectively (p < 0.001). The extent of induction did not vary between carriers of *1/*1 or carriers of a single variant allele.

Conclusion: Dicloxacillin induces warfarin oral clearance by 45%. Consequently, INR is significantly reduced. Phenytoin oral clearance and the formation clearance of its main metabolite were increased by 40%. The dose of CYP2C9 substrates characterized as NTI should be increased whenever dicloxacillin is prescribed.