Basic Research On Biopharmaceutic And Pharmacokinetic Characteristics Of Oxymatrine

Basic and clinical research suggests that oxymatrine (OM) and matrine (M) have a variety of pharmacological activities, including anti-cancer, anti-inflammatory, antipyretic, analgesic and anti-arrhythmia effects and immune regulation, anti-virus properties, hepatocyte-protected effect and anti-hepatic fibrosis action. The risk of drug interaction of OM increases along with its wide application in the clinic. The main objectives of this research were to study and clarify the biopharmaceutics and pharmacokinetics characteristics of OM and its metabolite M, in order to guide clinical medication and design of dosage forms.OM is a polar alkaline with high hydrophilicity, which can dissolve in chloroform, and soluble in 20% NaOH solution. A quantitative assay of OM and M in biological specimen was established on their characteristicsEverted gut sac and Caco-2 cell model were used to study the intestinal absorption kinetics of OM and M. OM and M was absorbed through the epithelia mostly by paracellular and transcellular pathway, respectively. Temperature and pH affected their member transport significantly (p<0.05). Neither P-gp nor BSA had influence on OM or M efflux from basolateral side to apical side (p>0.05).The first-pass metabolism of OM and M were not observed in enterocytes, so low potential of drug interaction existed in intestinal absorption process. OM and M can be absorbed by different position of rat intestine, which provide a theoretical basis for sustained and controlled release dosage forms of OM.A set of test drugs including OM, M andβ-blockers was used to evaluate the correlation between the human fraction absorbed (F_a%) and drug-biomembrane interaction scale system. The results showed the regression quality of systems with F_a% descended from Caco-2 cell monolayers, biopartitioning micellar chromatography (BMC), n-octanol/buffer distribution coefficient to immobilized artificial membrane Chromatography. So Caco-2 cell monolayers and BMC had better prediction power of hFA of quinolizidine alkaloids andβ-blockers.Following stomach-, duodenum- and ileum-specific delivery of OM to the rats, the metabolism of OM increased significantly as the microbial population multipled and anaerobic environment intensified. So it is suggested that the hepatopath should extend the time of therapy by administration with OM injection.It was shown from isolated perfused rat liver (IPRL) experiment that OM was actively transport into hepatocyte, that the kinetic model of OM in rat liver was consistent with the single compartment model, and that the elimination of OM from rat liver was dose dependent. Furthermore, OM was transformed to M in rat livers, and the metabolite was distributed in liver. Furthermore, it is suggested that the hepatopath with inordinate hepatic function should adjust the dosage of OM resulted from the significant difference in liver elimination of OM between the injury livers and intact livers.The mechanism of reduction of OM to M in liver microsomes was examined. Rat liver microsomes exhibited a reductase activity toward OM in the presence of NAD(P)H. The reductase activity was inhibited by air, and the activity was not abolished by boiling the microsomes. So the reduction of OM appears to proceed non-enzymatically, catalysed by the haem group of CYP450. It is suggested that coadministration with OM and inductor/inhibitor of microsomes should arouse the drug interaction.Bile excretion of OM was among its main excretion pathway, which was mediated by a carrier and depended on bilifaction. Six metabolites of first-phase reaction for OM were found in rat bile, most of which was M.The study on pharmacokinetics of OM in rat, beagle dog and human was shown that interspecies variation in pharmacokinetics was significant (p < 0.05). An allometric relationship between pharmacokinetic parameters and body weight is demonstrated. It is suggested that the pharmacokinetics of OM in human should be predicted from the pharmacokinetics in rat or dog. No statistically significant pharmacokinetic interaction occurred when lamivudine (3TC) and OM were given concomitantly to dogs by the intravenous or oral route. The present study supports the clinic practice in China that no dosage adjustment is required when lamivudine and oxymatrine are co-administrated.