Ezetimibe
The cholesterol-lowering effect of ezetimibe has been evaluated in mouse models of cholesterol metabolism in rhesus monkeys, dogs, rats and humans. Feed rhesus monkeys with cholesterol-containing food, imitating the diet of westerners. It was found that the ED50 (50% effective dose) of ezetimibe in inhibiting the increase of plasma cholesterol level in rhesus monkeys was 0.5? G /kg/ day, the dog's ED50 is 7? The ED50 (g/kg/day) of rats is 30? G/kg/ day, the ED50 of mice is 700? The results showed that ezetimibe was an effective cholesterol absorption inhibitor.
In the rat model, the metabolite of ezetimibe (ezetimibe-glucuronide) is as effective as ezetimibe in inhibiting cholesterol absorption when administered in the duodenum, which indicates that the activity of glucuronide metabolite is similar to that of patented drugs.
After taking ezetimibe (0.03 ~ 300mg/kg/ day) for 65438 0 months in dogs, the cholesterol concentration in bile can be increased by 2 ~ 4 times. After giving ezetimibe (300mg/kg/ day) to dogs for one year, no gallstones were found and no adverse effects were found on the hepatobiliary system. After taking ezetimibe (0.3 ~ 5mg/kg/ day) and feeding normal or high cholesterol feed for 65438 04 days, the cholesterol concentration in bile was not affected or decreased to normal level.
A series of preclinical studies show that ezetimibe can selectively inhibit the absorption of cholesterol. Ezetimibe inhibition [C]? The absorption of cholesterol does not affect the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol or fat-soluble vitamins A and D in the small intestine.
In the toxicity study of mice from 4 weeks 12 weeks, ezetimibe did not induce cytochrome P450 drug metabolism enzyme. The pharmacokinetic interaction between ezetimibe and HMG-CoA reductase inhibitor (parent drug or its active hydroxyl metabolite) was observed in rats, dogs and rabbits.
Animal toxicology
Central nervous system toxicity
Normal dogs take simvastatin 180mg/kg/ day (the average blood concentration produced by this dose is 12 times or higher than that produced by people taking 80mg/ day).
Normal dogs take 60mg/kg of drugs with chemical properties similar to this product every day (the average plasma drug concentration produced by this dose is 30 times or higher than that produced by people who take the highest dose (measured by total enzyme inhibitory activity), resulting in optic nerve degeneration (retinal-geniculate (nerve) fiber Wallerian degeneration). After the dog/kloc-0 was treated with 180 mg/kg/ day (the average plasma drug concentration produced by this dose was similar to 60 mg/kg/ day) for 4 weeks, Wallerian degeneration of vestibular (ear) cochlea and chromocytolysis of retinal ganglion cells also occurred: the average plasma drug concentration caused by this dose was similar to 60mg/kg/ day.
When simvastatin is taken at a dose of 360 mg/kg/ day (the average plasma drug concentration produced by this dose is 65438 04 times or higher than that produced by people taking 80mg per day), vascular injury (characterized by perivascular hemorrhage and edema, perivascular monocyte infiltration, perivascular fibrin deposition and small vessel necrosis) occurs in the central nervous system. Other drugs in this drug classification have also observed similar central nervous system angiopathy.
Female rats developed cataract symptoms after 50 and 100 mg/kg/day (AUC was 22 and 25 times of 80 mg/day, respectively), and dogs developed cataract symptoms after 90 mg/kg/day (19 times) for three months, at 50 mg/kg/day (5 times).
Carcinogenesis, Mutagenesis and Reproductive Toxicity
This product
The combination of ezetimibe and simvastatin has not been studied in animal carcinogenicity or fertility. In vitro microbial mutagenicity (Ames) of Salmonella typhimurium and Escherichia coli (with or without metabolic activation), the combination of ezetimibe and simvastatin showed no evidence of mutagenicity.
Chromosome aberration analysis of human peripheral blood lymphocytes in vitro showed that ezetimibe and simvastatin (with or without metabolic activation) had no induction effect. In the mouse micronucleus test, the dose of ezetimibe and simvastatin (1: 1) reached 600 mg/kg, and there was no genotoxicity.
Ezetimibe
Rats were given ezetimibe by mixed feeding method, male rats were given 1500 mg/kg/ day, and female rats were given 500 mg/kg/ day (the total AUC of ezetimibe was 0-24 hours, which was about 20 times of the daily exposure of 10mg), and the carcinogenic test was carried out100. At the same time, the dietary carcinogenesis of mice was studied for 104 weeks, and the dose reached 500 mg/kg/ day (calculated by the total AUC of ezetimibe for 0-24 hours, it was about 150 times of the daily exposure of human beings). For rats and mice treated with drugs, there is no statistically significant increase in the incidence of tumors.
No mutation was observed in bacterial mutagenicity test (Ames) with or without metabolic activation with Salmonella and Escherichia coli in vitro. In the human peripheral blood lymphocyte test (with or without metabolic activation), the chromosome aberration result is negative. In addition, the results of mouse micronucleus test in vitro were negative.
In the study on the reproductive capacity of rats taking ezetimibe orally, when the dose of ezetimibe in male or female rats reached 1000 mg/kg/ day, no reproductive toxicity was observed (based on the total AUC of ezetimibe for 0-24 hours, it was about 7 times of the daily exposure 10mg).
simvastatin
The carcinogenicity test of simvastatin 25, 100 and 400 mg/kg/ day on mice for 72 weeks showed that its average blood concentration was about 1, 4 and 8 times higher than that of oral 80 mg (total inhibitory activity AUC). In high-dose female group and middle-high-dose male group, the incidence of liver cancer increased significantly, and the highest incidence rate in male group was 90%. The incidence of hepatic adenoma in low-dose and high-dose female groups increased significantly. The incidence of pulmonary adenoma in female and male middle and high dose groups also increased significantly. Compared with the control group, the adenoma of accessory lacrimal gland (the gland of rodent eyes) in high dose male group increased significantly. 25 mg/kg/day group had no effect on carcinogenicity. In the 92-week study, the dose of mice was 25 mg/kg/ day, and there was no carcinogenic effect (calculated by AUC, the average blood concentration was twice that of simvastatin 80 mg taken orally by humans).
In the study of simvastatin 25 mg/kg/ day for two consecutive years, the incidence of thyroid follicular adenoma in female rats increased significantly. According to AUC calculation, the exposure level is 1 1 times higher than that of people taking simvastatin 80 mg.
Hepatocellular adenoma and cancer (in two female dose groups and 65,438+000 mg/kg/day male dose group) were found in the carcinogenicity study of rats for two years. In the male and female dosage groups, the number of thyroid follicular cell adenoma and thyroid follicular cell carcinoma increased in the female 100 mg/kg/ day group. Other HMG-CoA reductase inhibitors increase the incidence of thyroid tumors. Its blood drug concentration (AUC) is equivalent to 7 and 15 times (male) and 22 and 25 times (female) of the average plasma drug exposure level of 80 mg per day.
No evidence of mutagenicity was observed in rats or mice with or without liver metabolic activation. In addition, no mutagenicity was found in the alkali elution analysis of rat hepatocytes in vitro, the forward mutation study of mammalian V-79 cells, the chromosomal mutation study of CHO cells in vitro or the chromosomal mutation analysis of mouse bone marrow cells in vivo.
After 34 weeks of simvastatin 25 mg/kg (calculated by AUC of patient dose, it is 4 times of the maximum exposure level of 80mg/ day), the fertility of male rats decreased. However, in the subsequent fertility experiment of male rats, the same dose of simvastatin *** 1 1 week (the complete cycle of sperm development, including epididymal development and maturation) was not observed. No changes in rat testis were observed under these two experimental microscopes. 180 mg/kg/day (this dose is 22 times higher than the maximum exposure level of 80 mg/kg/day for human consumption), and the degeneration of vas deferens (necrosis and injury of seminiferous epithelium) was observed. When dogs took 10 mg/kg/ day, testicular atrophy, decreased spermatogenesis, spermatocyte degeneration and giant cell formation related to drugs were observed (calculated by AUC, it was about twice as much as the human exposure dose of 80 mg/ day). The clinical significance of the above findings is unclear.
clinical pharmacology
Mechanism of action
This product
Plasma cholesterol comes from intestinal absorption and endogenous cholesterol synthesis. This product is a lipid-lowering drug, which contains ezetimibe and simvastatin, and the two mechanisms complement each other. This product can reduce the levels of plasma total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, triglyceride and non-high density lipoprotein cholesterol by inhibiting the absorption and synthesis of cholesterol, and can increase the level of high density lipoprotein cholesterol.
It has not been proved that this product is more beneficial than simvastatin in cardiovascular morbidity and mortality.
Ezetimibe
Ezetimibe can reduce the cholesterol level in the blood by inhibiting the absorption of cholesterol in the small intestine. At present, the molecular target of ezetimibe is the sterol carrier Nieman-Peak C1-like1(NPC1L1), which is related to the intestinal absorption of cholesterol and phytosterols. In a two-week clinical study of 18 patients with hypercholesterolemia, compared with placebo, this product inhibited the absorption of cholesterol in small intestine by 54%. This product has no clinical effect on the plasma concentrations of fat-soluble vitamins A, D and E, and will not reduce the production of adrenal corticosteroids.
Ezetimibe adheres to the brush border of villous epithelium of small intestine, which inhibits the absorption of cholesterol, thus reducing the transport of cholesterol from small intestine to liver. This reduces the storage of cholesterol in the liver and increases the clearance of cholesterol in the blood; This unique mechanism of action is just complementary to that of HMG-CoA reductase inhibitor. (See Clinical Studies)
simvastatin
Simvastatin inhibits HMG? CoA is converted into mevalonate (the early step of cholesterol biosynthesis pathway) to reduce cholesterol content. In addition, simvastatin can reduce VLDL and TG levels and increase HDL-C.