Pharmacology and toxicology of duloxetine hydrochloride enteric-coated capsules

Pharmacological Action Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). The exact mechanism of duloxetine's antidepressant and central analgesic effects is unclear, but it is thought to be related to its enhancement of serotonin and noradrenergic functions in the central nervous system. The results of preclinical studies show that duloxetine is a strong inhibitor of serotonin and norepinephrine reuptake in neurons, and its inhibitory effect on dopamine reuptake is relatively weak. The experimental results in vitro show that duloxetine has no obvious affinity with dopaminergic receptor, adrenergic receptor, cholinergic receptor, histamine receptor, opioid receptor, glutamate receptor and GABA receptor. Duloxetine does not inhibit monoamine oxidase. Toxicological study of genotoxicity: The results of Duloxetine Ames test, forward gene mutation test of mouse lymphoma cells, unscheduled DNA synthesis test of rat hepatocytes, sister chromatid exchange test of China hamster bone marrow cells and mouse micronucleus test were all negative. Reproductive toxicity: before and after mating, the oral dose of duloxetine in female or male rats reached 45mg/kg/ day (calculated by mg/m[sup]2[/sup], which was 7 times of the maximum recommended dose of 60 mg/ day [MRHD] for human beings), and had no effect on mating or fertility. In the teratogenic sensitive period, rats and rabbits took duloxetine orally for 45mg/kg/ day (calculated by mg/m[sup]2[/sup], the rats and rabbits were 7 times and 15 times of MRHD, respectively), which showed that the fetus lost weight and no teratogenic effect was observed. The non-impact dose is 10mg/kg/ day (calculated by mg/m[sup]2[/sup], rats and rabbits are equivalent to 2 times and 3 times of MRHD respectively). When duloxetine was given orally to perinatal rats at 30 mg/kg/ day (calculated by mg/m[sup]2[/sup], rats were equivalent to 5 times of MRHD), the survival rate after birth 1 day and the weight at birth and lactation decreased, and the no-impact dose was 10 mg/kg/ day. At the dose of 30 mg/kg/day, the behavior of young rats changed, showing an increase in reactivity, such as an increase in response to noise shock and a decrease in voluntary activities. There is no adverse effect on the growth and reproductive behavior of offspring after weaning. Carcinogenicity: Rats and mice ingested duloxetine for 2 years. When the dose of duloxetine is 140mg/kg/ day (calculated by mg/m[sup]2[/sup]), it is equivalent to 1 1 times of MRHD, and the incidence of hepatocellular adenoma and hepatocellular carcinoma increases. When the non-impact dose is 50mg/kg/ day (calculated as mg/m) and the duloxetine dose is 100mg/kg/ day (calculated as mg/m), the doses of female rats and male rats are 27 and 36mg/kg/ day (calculated as mg/m[sup]2[/sup], respectively, which are equivalent.