Effect Of Fluvoxamine On The Pharmacokinetics And Pharmacodynamics Of Clopidogrel In Rats

Objectives: Explore the effect of fluvoxamine on the pharmacokinetics and phamacodynamics of clopidogrel in rats.Methods:(1) The effect of fluvoxamine on the pharmacokinetics of clopidogrel: A accurate, rapid and sensitive LC/MS/MS method for the quantitation of clopidogrel in rat plasma has been established. Twenty-four male Wistar rats were randomly divided into three groups. Control group(clopidogrel without fluvoxamine), low dose group(clopidogrel with 4.5 mg/kg of fluvoxamine) and high dose group(clopidogrel with 27 mg/kg of fluvoxamine). Rats were given normal saline or fluvoxamine for 7 days. On the seventh day, the control group(n=8) received a dose of clopidogrel(6.75 mg/kg) 1 h after normal saline. The low dose group(n=8) and the high dose group(n=4) received fluvoxamine 1 h prior to clopidogrel(6.75 mg/kg) administration. Blood samples(0.5 m L) were collected into 1.5 m L heparinized and dichlorvos-treated(terminal concentration of dichlorvos: 200 ?g/m L) Eppendorf tubes at the following times: immediately before administration, and at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12, 24, 36 and 48 h after dosing. After a simple protein precipitation with methanol, the analytes were injected onto the LC/MS/MS system for the quantification of clopidogrel carboxylic acid in rat plasma. Clopidogrel carboxylic acid was used for the pharmacokinetic study of clopidogrel in rats.(2) The effect of fluvoxamine on the pharmacodynamics of clopidogrel: Sixteen male Wistar rats were randomly divided into four groups(four rats each group). Control group(normal saline), clopidogrel group, low dose group(clopidogrel with 4.5 mg/kg of fluvoxamine) and high dose group(clopidogre with 27 mg/kg of fluvoxamine). Rats were given normal saline or drugs for 7 days. For oral dosing, clopidogrel(6.75 mg/kg) and fluvoxamine maleate dissolved in normal saline were given to the rats by gavage. On the seventh day, after 1 h of administration of normal saline or drugs, 1.8 m L of blood sample was collected from the abdominal artery of anesthetized rats directly into 0.2 m L of 3.8% sodium citrate solution Eppendorf tubes. Preparation of poor plasma(PPP) and platelet platelet rich plasma(PRP), ADP induced platelet aggregation was measured to compare influence of fluvoxamine on the pharmacological effect of clopidogrel.Results: Compared with the control group, After pretreatment with high dose of fluvoxamine(27mg/kg), there were significant increases in the AUC0-t(from 12945±4139 to 25233±5380?g/L*h; p<0.05), AUC0-?(from 12952±4149 to 25558±5324?g/L* h; p<0.05) and t1/2(from 2.8±1.4 to 7.8±1.6 h; p<0.05) of clopidogrel carboxylic acid. The pharmacokinetic data for clopidogrel carboxylic acid showed significant decreases in CLz/F(from 0.58±0.23 to 0.27±0.05L/kg; p<0.05) after pretreatment with high dose of fluvoxamine. Pharmacodynamic studies that measure platelet aggregation percentage(from 21.63±6.05% to 45.98±5.11%; p <0.01)show that high doses of fluvoxamine significantly inhibit the effect of clopidogrel.Conclusions: The pharmacokinetics and pharmacodynamics of clopidogrel were significantly affected by high doses of fluvoxamine. This study indicated that potential drug–drug interaction between fluvoxamine and clopidogrel should be taken into consideration in clinical use.