Pharmacological action Pregabalin has high affinity with α2-δ site (the auxiliary subunit of voltage-gated calcium channel) in the central nervous system. The mechanism of action of pregabalin is not clear, but the results of transgenic mice and structurally related compounds (such as gabapentin) indicate that the analgesic and anticonvulsant effects in animal models may be related to the combination of pregabalin with α2-δ subunit. In vitro studies show that pregabalin may reduce the calcium-dependent release of some neurotransmitters by regulating the function of calcium channels. Although pregabalin is a structural derivative of the inhibitory neurotransmitter γ -aminobutyric acid (GABA), it does not directly bind to GABAA, GABAB or benzodiazepine receptors, does not increase the GABAA response of neurons in vitro, does not change the concentration of GABA in the brain of rats, and has no acute effect on GABA uptake or degradation. However, it was found that the density of GABA transporters and the rate of functional GABA transporters increased after long-term exposure of cultured neurons to pregabalin. Pregabalin does not block sodium channels, has no activity on opioid receptors, does not change cyclooxygenase activity, has no activity on dopamine and serotonin receptors, and does not inhibit the reuptake of dopamine, serotonin or norepinephrine. Toxicological study on genotoxicity: In vitro studies show that pregabalin has no mutagenic effect on bacteria and mammalian cells, while in vivo and in vitro studies show that pregabalin does not cause chromosome aberration in mammals and does not induce unscheduled DNA synthesis in rat or mouse hepatocytes. Reproductive toxicity: Male rats took pregabalin orally (50-2,500 mg/kg) before and during mating, and mated with female rats without pregabalin, which showed various adverse effects on reproduction and development, including decreased sperm count, decreased sperm motility, abnormal increase of sperm, decreased fertility, increased loss rate before implantation, decreased litter size, decreased fetal weight and increased incidence of fetal abnormalities. During the study period (3-4 months), the effects on sperm and fertility parameters were reversible. At the no-effect dose (100 mg/kg) of male rats, the plasma exposure (AUC) of pregabalin is about three times that of human beings. In addition, in the general toxicity study of 4 weeks or more, the histopathological examination of male rats showed that the reproductive organs (testis and epididymis) had adverse reactions at the dose of 500- 1250 mg/kg, and the no-impact dose was 250 mg/kg, which was about 8 times of the human plasma exposure at MRD. Female rats were given pregabalin 500 mg/kg, 65438 mg/kg+0250 mg/kg and 2500 mg/kg orally before mating, during mating and early pregnancy. Estrus cycle disorder and mating days increased at various doses, and embryos died at high doses. The plasma exposure of low dose pregabalin is about 9 times that of human MRD, and the no-impact dose has not been determined. When the plasma exposure (AUC) of pregabalin in pregnant rats and pregnant rabbits is equal to or greater than 5 times of MRD, the incidence of fetal structural malformation and other developmental toxicity increases, including fetal death, growth retardation and functional damage of nervous and reproductive systems. During organogenesis, pregnant rats were given pregabalin 500 mg/kg, 1250 mg/kg or 2500 mg/kg orally. The plasma exposure (AUC) of low-dose pregabalin is about 17 times that of MRD population. When the dose was ≥ 1250 mg/kg, the incidence of specific skull abnormalities caused by abnormal early ossification (premature fusion of zygomatic bone and nasal bone suture) increased. Bone variation and ossification delay can be seen in all doses. At high doses, fetal weight decreased. The effect dose of pregabalin on embryonic-fetal development in rats has not been determined. During organogenesis, pregnant rabbits were given pregabalin 250,500 or 1250 mg/kg orally. At high dose, the incidence of fetal weight loss, delayed ossification, skeletal malformation and visceral variation increased. The dose that has no effect on the development of rabbits is 500 mg/kg, and the plasma exposure in MRD is about 16 times of the human exposure. In the perinatal toxicity test, rats were given pregabalin 50, 100, 250, 1250 or 2500 mg/kg orally. When ≥ 100 mg/kg, the growth of offspring slowed down, and when ≥250 mg/kg, the survival rate of offspring decreased. When ≥ 1250 mg/kg, the survival rate of offspring was significantly affected. At the highest dose, the mortality rate of littermates was 100%. When the offspring were tested as adults, abnormal neurobehavior (decreased auditory panic response) was observed at ≥250 mg/kg, and reproductive function was impaired at 1250 mg/kg (decreased fertility and litter size). The dose that has no effect on the perinatal development of rats is 50 mg/kg, and the plasma exposure in MRD is about twice that of human body. Carcinogenicity: The incidence of angiosarcoma increased in a dose-dependent manner when the doses of B6C3F 1 and CD- 1 mouse pregabalin were 200 mg/kg, 1000 mg/kg and 5000 mg/kg for two consecutive years. At the lowest dose, the plasma exposure (AUC) of mice is almost the same as that of MRD, and the no-impact dose induced by angiosarcoma in mice has not been determined. Wistar rats were given pregabalin by mixed diet for two years. The dosage of male rats was 50 mg/kg, 150 mg/kg, and that of female rats was 100 mg/kg, 300 mg/kg and 900 mg/kg. The maximum dose is equivalent to 14 times and 24 times of the maximum residue limit, respectively. No increase in tumor incidence was found. Other toxic skin toxic skin lesions can be seen in repeated toxicity tests in rats and monkeys, and the degree of lesions ranges from erythema to necrosis, and the reasons are not clear. The dose of pregabalin causing skin damage is twice that of MRD. When the plasma exposure (AUC) of pregabalin is 3-8 times that of MRD, more serious skin lesions, including necrosis, will occur. In clinical trials, the incidence of skin injury has not increased. In two carcinogenicity tests on Wistar rats, eye injuries (characterized by retinal atrophy (including loss of photoreceptor cells) and/or corneal inflammation/mineral deposition) can be observed. The plasma exposure (AUC) of pregabalin at the time of change is more than twice that of MRD, and the influence dose has not been determined. No similar lesions were found in the carcinogenicity test of the two strains of mice or in the carcinogenicity study of 1 year monkeys.