Effects Of Statins On The Pharmacokinetics And Pharmacodynamics Of Clopidogrel In Vivo

Background: Clopidogrel is widely used as an antiplatelet drug in clinical practice.Some patients have low response or even no response to clopidogrel,that is,clopidogrel resistance(CR).Drug interaction is one of the potential causes of clopidogrel resistance.The effect of statins on clopidogrel is controversial,possibly due to there are many confounding factors in patient-based clinical studies.Currently,comparative studies on the effects of statins based on CYP3A4 metabolism and non-CYP3A4 metabolism on the antiplatelet function of clopidogrel are lacking.Objective: To investigate the effects of atorvastatin and rosuvastatin on the pharmacokinetics and pharmacodynamics of clopidogrel in healthy subjects,and to observe the safety of co-administration.Methods:(1)Twelve healthy subjects were randomly divided into two groups using a randomized,three-period,two-cross drug administration design.In the first period,clopidogrel 300 mg was taken orally in both groups.In the second period,two groups were given atorvastatin(80 mg/d)or rosuvastatin(20 mg/d)for 7 days,respectively,and clopidogrel 300 mg in combination on day 7.In the third period,two groups were interchangeably given rosuvastatin(20 mg/d)or atorvastatin(80 mg/d)for7 days,and clopidogrel 300 mg in combination on day 7.The concentrations of clopidogrel and its active metabolites in plasma were determined by high performance liquid chromatography-mass spectrometry,and inhibition of platelet aggregation(IPA)and platelet reactivity index(PRI)were determined by light transmission aggregometry(LTA)and vasodilator-stimulated phosphoprotein(VASP)phosphorylation method.The pharmacokinetics and pharmacodynamics of clopidogrel were evaluated.(2)The polymorphism loci of CYP2C19 *2,*3 and *17genes were classified by first-generation sequencing technology,and different metabolic types were further analyzed.Results:(1)In terms of pharmacokinetics,compared with clopidogrel alone,the production of active metabolites of clopidogrel was reduced with co-administration of atorvastatin or rosuvastatin.In terms of pharmacodynamics,the change trend of IPA within 6h after the combination of atorvastatin and rosuvastatin was consistent,and reached the maximum value at 4h after co-administration of atorvastatin and rosuvastatin,while IPA reached the maximum value at 2h after clopidogrel alone.There was no significant difference in the maximum IPA between clopidogrel alone and co-administration of atorvastatin and rosuvastatin.VASP phosphorylation was detected at 0h,6h and 24 h,and the results showed no significant difference.(2)In subjects with CYP2C19 homozygous wild-type(*1/*1)and loss-of-function allele homozygotes or heterozygotes(*2/*2,*1/*2,*1/*3),we both observed a similar trend with overall,but some of the differences were not statistically significant.(3)Three subjects experienced a 4.0 ～ 9.1 fold increase in creatine kinase isoenzymes when treated with co-administration of atorvastatin.Conclusions:(1)The negative effects of atorvastatin and rosuvastatin on clopidogrel were both observed in healthy subjects with CYP2C19 homozygous wild-type(*1/*1)and carring loss-of-function allele of CYP2C19(*2 or *3).(2)When clopidogrel is used in combination with statins,it is necessary to guard against the increase of creatine kinase isoenzymes.