The Effect Of Aspirin Alone And Coadministration With Erythromycin Ethylsuccinate On Rats Hepatic Enzymes

Cytochrom P450(CYP450)is most important among mixed function oxidases in liver microsome,containing many isoenzymes of different specifical substrates.CYP450 plays an important role in biotransformation of mang drugs.CYPl,CYP2,CYP3 are main subfamilies involved in many drugs metabolism.CYP450 is very important in pharmacology and toxicology studies.Because CYP450 activities can be induced or inhibited by many chemicals,causing the change of drugs metabolism,accumulation of drugs and toxicity or adverse reactions,so the study of CYP450 activities and drug interactions becomes focus. First of all,understanding of CYP450 induction and inhibition,we can direct clinical coadministration of drugs reasonably. According to the extent of induction or inhibition,we can change drug doses to prevent from serious side effects or therapeutic failure due to deficient therapeutic concentration.Secondly,from molecular biology view,we can have a further study of developing mechanism of diseases,especially tumor. Through understanding the effect of CYP450 on transformation of precarcinogens and pretoxicity in vivo,we may lower the incidence of tumor by hibition of CYP450 purposefully to reduce toxicology and carcinogens.Cardio-cerebral vascular disease has become one of fetal factors because of its high incidence. Drug prevention is useful to change bad tendency and delay disease development. Aspirin(Asp)is a non-selective inhibitor of cyclooxygenase. Experimental pharmacology and clinical practice show that low dose Asp can inhibit COX-1 in thrombocyte and can decrease TXA2 and platelet aggregation,then prevent invasion of cardio-cerebral vascular disease and transient ischemic attack. Asp was found effective as an antiplatelet drug in first and second preservation of myocardial infarction,ischemic cerebrovascular disease for high-risk patients. Taking one or two Asp(25～50mg) can reduce 25～33% Cardio-cerebral vascular events. With serious aging of the population and enlarging patients,Asp becomes a common drug for the aged because of its wide indications,low price and high potency ratio. Drug coadministrations are common in the aged. Drug interaction has become the hot spot.Through clinical drug administrations analysis of the aged, we found Asp had a high frequency interaction with other drugs. Respiratory infections is common for the aged,erythromycin ethylsuccinate as a wide-used antibacterial anti-inflammatory drug, interacts with Asp.Also,Asp as a wide-used antipyretic analgesic drug,interacts with erythromycin ethylsuccinate for fever patients. Coadministration of Asp and erythromycin ethylsuccinate is common in many prescriptions. So the article is to study how Asp(used alone and combined with Erythromycin Ethylsuccinate)effects CYP450 activities, to find out CYP450 isoenzymes involved in metabolism,to identify mechanism of drug action,to find out whether metabolic interaction exist between the two drugs,to forecast drug interactions process. So the study is of great clinical importance in directing clinical rational drug use.1 Use condition and reasonable analysis of drug use for the aged in hospitalCollecting 3012 prescriptions(2006.12.05～09)of health care pharmacy randomly, copy the informations(names,genders,ages,prescription contents and so on)into clinical drug advisory software and inspect rationality of clinical drug administration of the aged. We found that many muti-drug administrations and high rates of potiential adverse drug interactions exist among the aged. Through offering pharmaceutical care services and making full use of prescription review system to guide correct and safe drug use.2 Effects of Aspirin on rat hepatic enzymes activities and CYP subtype genes expressionsUse ultraviolet spectrophotometry and fluorospectrophotometry to study rat hepatic enzymes activities by different doses Asp.To investigate whether Asp inhibit or induce rats hepatic enzymes,whether the effects depend on gender,drug dose and use time.Use RT-PCR to identify rat hepatic CYP1A2,CYP2E1,CYP3A1 genes expressions and effects by different doses Asp. Different doses Asp induced rat hepatic enzymes activities,low dose Asp effects weakly,high dose Asp effects notably. Differences exist between male and female rats,and induction strength extends with drug dose and use time. Middle and High dose group rat hepatic CYP2E1 mRNA express much higher than blank group(P< 0.01) ,high dose group rat hepatic CYP3A1 mRNA express higher than blank group (P< 0. 05) ,there is little difference in CYP1A2 mRNA expression.3 Effects of Asp coadministration with erythromycin ethylsuccinate on rat hepatic enzymes activities and CYP subtype genes expressionsThe methods is similar to the second part.Asp(Alone and combined with erythromycin ethylsuccinate)effect rat hepatic enzymes differently: erythromycin ethylsuccinate inhibits rat hepatic ERD and EROD activities more obviously and can offset induction of Asp. Asp induces rat hepatic ADM and GST activities and can offset inhibition of erythromycin ethylsuccinate. Erythromycin ethylsuccinate group rat hepatic CYP mRNA expression degrades and CYP3A1 mRNA degrades obviously(P<0.05) .Asp group rat hepatic CYP mRNA expression raises and with CYP2E1 mRNA raises obviously(P< 0.05) .Combination group rat hepatic CYP3A1 mRNA expression is lower than blank group(P< 0.05),but higher than erythromycin ethylsuccinate group; CYP2E1 mRNA expression is higher than blank group(P<0.05) ,but lower than Asp group.