The Effect Of Marine Sulfated Polysaccharide 916 On Pharmacokinetics Of Simvastatin In Rats

Simvastatin is the drug of first choice for hypercholesterolemia, it can effectively reduce morbidity and death rate of coronary heart disease, and is also used to treat hyperlipemia.916 is one kind of polyanion sulfated amino polysaccharide which is derived from marine chitin and by ways of multiple molecular modification. 916 shows good antiatherosclerotic activity. The drug interaction caused by drug combination, which changes the curative effect and causes side effects and toxicity has attracted great attention.In this paper, using rats as the subject HPLC method is used to study the effect of 916 on the pharmacokinetics of Simvastatin, which will be used as a reference for the clinic study.The experiment is divided into Simvastatin group and Simvastatin plus 916 group, and change of drug-time curve of the rats with different sexes is studied. According to the results, the distribution of Simvastatin in liver and small intestine and discharge in dung and urine of the male rats are studied. Finally the effect of 916 on the activity of liver cytochrome P450 subtypes CYP1A2, CYP2E1 and CYP3A is researched through the metabolism change of Caffeine, Chlorzoxazone and Dapsone.The main pharmacokinetic parameter Cmax, t1/2, AUC0-∞of female rats Simvastatin group and Simvastatin plus 916 group are separately (144.66±22.31) ng?mL-1, (4.74±1.19) h, (1.62±0.47)μg?h?mL-1 and (166.03±59.99) ng?mL-1, (4.27±1.15) h, (1.20±0.33)μg?h?mL-1, and the t-test shows that the difference between the main pharmacokinetic parameter has no statistic meaning(p>0.05); while these main pharmacokinetic parameter Cmax, t1/2, AUC0-∞of male rats comparison and 916 group are separately (165.91±52.50) ng?mL-1, (14.98±6.64) h, (2.19±0.62)μg?h?mL-1and (84.95±28.39) ng?mL-1, (4.26±0.48) h, (0.41±0.09)μg?h?mL-1, and the t-test shows that the difference between the main pharmacokinetic parameter has obvious statistic meaning(p<0.01), which suggests that 916 has strong effect on the pharmacokinetics of Simvastatin in male rats. The drug content in liver and small intestine of male Simvastatin plus 916 group is higher than Simvastatin group, and the drug content in liver in male Simvastatin plus 916 group at 0.5h is 5.3 times of Simvastatin group, which shows high statistic meaning (p<0.01). The drug content in small intestine at 6h has the trend of increase, and it greatly enhances the drug cumulation.The discharge experiment shows that the drug prototype of Simvastatin discharged though urine has no significant change, while that discharged through dung is obviously increased, the cumulation of drug prototype discharged though dung in Simvastatin plus 916 group is 2.7 times of Simvastatin group.The liver microsomes experiment shows that 916 has no effect on the activity of liver cytochrome P450 subtypes CYP1A2, CYP2E1 and CYP3A.Results: 916 has obvious effect on the pharmacokinetics of Simvastatin in male rats, but none in female rats. 916 has no effect on the activity of liver cytochrome P450 subtypes CYP1A2, CYP2E1 and CYP3A, but it adds the drug content in male rat liver and small intestine, and greatly increased the discharge procedure of simvastatin in male rats, which causes the reduction of t1/2 and AUC.