Study of the fluvastatin effect on phenytoin disposition in healthy male rabbits

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Original Article

Author Details : Issam Abushammala, Abeer Mahmoud

Volume : 5, Issue : 5, Year : 2017

Article Page : 222-226

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Abstract

Introduction: Drug-drug interaction is a serious problem facing patients with chronic diseases like epilepsy; it is also an important reason for drugs refusal and withdrawal from markets. That makes the study and evaluation of the probability of drug-drug interaction is an important research area. Phenytoin is one of antiepileptic drugs which are widely used for seizure relieve. Fluvastatin is a lipid lowering drug that acts by competitively inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase that makes fluvastatin as a potent lipid lowering drug and prevents cardiovascular diseases. The goal of this study was to evaluate the effect of Fluvastatin on daily oral administered phenytoin pharmacokinetic in therapeutic dose and studying the changes in phenytoin serum concentrations when adding oral Fluvastatin to Rabbits.
Materials and Method: An in-vivo drug-drug interaction study was conducted in healthy male rabbits between fluvastatin and phenytoin. Parallel designed studies for the two groups of rabbits were conducted. Twelve rabbits were divided into two groups. The first group (control group) received phenytoin of 25 mg/Kg/day for 14 days. On the day 15, blood serum samples were collected over a period of 24.0 hours after the last dose according to the designed time schedule 0.0, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 9.0, 12.0 and 24.0 hours. The second group (tested group) received phenytoin of 25 mg/Kg/day for seven consecutive days and at day 8 was added fluvastatin at 4 mg/Kg/day until day 14. On the day 15, blood serum samples were collected at the same time schedule as in the first group. Chemiluminescent enzyme immunoassay (CLEIA) was used to measure serum phenytoin levels. Non-compartmental analysis by using WinNonlin was used to determine the different pharmacokinetic parameters such as C_max, T_max, AUC _0-24, t _1/2 and k_e.
Results: Significant increases were reported in tested group related to reference group in C_max and AUC _0-24 of phenytoin. In control group the parameters were: C_max= 5.18 µg/ ml and AUC _0-24= 80.99 µg. h/ml. In the tested group these parameters increased significantly to: C_max= 6.96 µg/ ml and AUC _0-24= 121.93 µg. h/ml. In this group, significant decrease was also reported in k_e (0,019 h^-1 vs 0,046 h^-1 in control group). Moreover, the t _1/2 was doubled in tested group (41, 6 hours vs 20, 44 hours in control group). The decrease in T_max was insignificant, it decreased from 11.18 hours in the control group to 10 hours in the tested group.
Conclusion: Fluvastatin alters the pharmacokinetic parameters of phenytoin to significant levels.

Keywords: Phenytoin, Fluvastatin, Drug-drug interaction, Pharmacokinetic parameters, CYP2C9

How to cite : Abushammala I, Mahmoud A, Study of the fluvastatin effect on phenytoin disposition in healthy male rabbits. J Pharm Biol Sci 2017;5(5):222-226

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