Abstract

PHARMACOKINETIC INTERACTION STUDY BETWEEN CLOPIDOGREL AND PHENYTOIN IN HEALTHY MALE RABBITS

Issam Abushammala*, Alaa Abusoud and Kamal Fakher Abu Shammaleh

ABSTRACT

Introduction: This study was conducted to investigate the effect of clopidogrel – CYP2 C19 inhibitor on the pharmacokinetics (PK) of phenytoin in healthy male rabbits. The main aim of this study is to determine the PK of phenytoin after its daily oral administration when concomitantly administered with cytochrome CYP2 C19 inhibitor clopidogrel. Methodology: An in-vivo parallel designed drug-drug interaction (DDI) study was conducted in healthy male rabbits. Twelve rabbits were divided into two groups. The first group (The control group) received phenytoin of 30 mg/Kg/day for 14 days. On the day fourteen, blood samples were collected according to the time schedule 0.0, 1.30, 3.0, 4.30, 6.0, 7.30, 9.0, 12.0, 24.0, 36.0 and 48.0 hours (h) after the last dose. Chemiluminescent enzyme immunoassay (CLEIA) was used to measure phenytoin concentration in serum. The second group (The tested group) received phenytoin of 30 mg/Kg/day for seven constitutive days and at day 8 clopidogrel of 1.1 mg/Kg/day was added to the phenytoin until the day fourteen, then blood samples were collected as in the first group at the same time schedule for 48 h. Non-compartmental analysis by using winnonlin was used to determine the different PK parameters such as Cmax, Tmax, AUC0-48, t1/2 and ke. Results: Significant increase were reported in the second group related to first group in Cmax, AUC 0-48 and t1/2. In the first group the parameters were: Cmax=11.15μg/ ml and AUC 0-48=174.09 μg.h/ml. In the second group the last parameters increased significantly to: Cmax=11.66 μg/ ml, AUC 0-48=198.1 μg.h/ml and significant decrease was also reported in ke. In the first group ke=0.029 h-1 and decreased to ke=0.0185h-1 in the second group. The values of t1/2 were increased from t1/2 = 25.63 h in the first group to 36.51 h in the second group. There was insignificant change in Tmax. Conclusion: Clopidogrel alters the PK parameters of phenytoin to a significant levels.

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