Toxicokinetics And Toxicodynamics Of Lovastatin In Male Bama Miniature Pig

The search for an optimal experimental model in pharmacology and toxicology is recently focused on minipigs as they seem not only to be an alternative source of cells and tissues for xenotherapy but also an alternative species for studies on drug metabolism in human due to similarities between minipig and human drug metabolic systems.Although there is considerable resource in China,none has been used in pharmacology or toxicology. Lovastatin,a specific inhibitor of HMG-CoA reductase(the rate-limiting enzyme in cholesterol biosynthesis),has been shown to be an effective agent in lowering serum cholesterol in animals and humans and thus represents a promising approach to the treatment and prevention of caidiovascular disease.We mainly studied animals' toxic response when they were exposed in the exceed therapy dose of lovastatin,and simultaneously studied the expose profile of drug in animals,in order to guide the clinical safe medication of drug correctly.A highly sensitive and rapid method using reversed-phase liquid chromatography has been developed for the quantitative analysis of lovastatin in Bama miniature pig plasma. Plasma was processed using liquid-liquid extracion.The processed sample was chromatographed on Agilent ODS Hypersil C18.The mobile phase is mixture of acetonitril and sodiumdihydrogen phosphate(55:45;pH4.5),at a flow rate of 1.0ml/min.The wavelength of UV detecion was 238nm.Column temperture was 50±0.5℃.The lowest detectable concentration of lovastatin was 0.01μg/ml.The recovery rate of these methods is (95.4±4.77)%,RSD of intra-day and inter-day were less than 2%.Each sample was chromatographed within about 10.0min.First,we had carried out a study of lovastatin,an HMG-CoA reductase,in bama miniature pig.It indicates that monocyte and eosinophilia increased,but red blood counts in bama miniature pig given with 1.25g.kg^-1 lovastatin declined compared with control after medication,and have a significant difference in statistics.It shows that lovastatin have a little hemolysis trend but not remarkable.The other detection items are all natural during the medication.The pathological histology analysis result shows that there is some morphological abnormalities and chatacteristic pathological change in the major target organ liver,kidney,no similar morphologic alterations have been observed in rodents,dogs,rabbits or monkeys during the preclinical safty assessment of lovastatin.The livers are lesioned associated with up to 2-6 fold eleations in serum aspartate,alkaline phosphatase and alanine aminotransferase activities,whereas the kidneys lesions resulted in accumulations of serum urea nitrogen and creatinine.The organ damage was probably preceded by a progressive decline in food consumption and loss of body weight.So,Bama miniature pigs could show some toxic reactions that observed in clinical therapy of lovastatin.Although myopathy isn't detected in bama miniature pig or other animals,myopathy is occasionally observed in clinical therapy.The preliminary toxicokinetics study in Bama miniature pig is carried out after medication.The main pharmacokinetic pharmeters of lovastatin were as follows:The distribution phase half life,t_1/2(α),is 0.858038h and elimination phase half life,t_1/2(β),is 6.802h;the Tmax,AUC_{0→∞},Cmax,CL(s) and V/F(c) are 0.665h,156.430(ug/ml)^*h, 26.625μg/ml,0.0325±0.00g/kg/h/(ug/ml),0.008±0.002(g/kg)/(ug/ml).It indicates that toxicokinetic model of lovastatin in Bama miniature pig is both first-order elimination and two-compartment model with oral administration.The distribution and target organ of lovastatin in Bama miniature pig are similar to human,but lovastatin could be rapidly eliminated in male Bama miniature pig.Bama miniature pig is especially suitable for long-term studies because of its inherent small size and ease for handling with.Our research indicates that Bama miniature pig is suitable for toxicological and toxicokinetical study in non-clinical testing programme.