Acute, subchronic oral toxicity, and genotoxicity evaluations of LPM570065, a new potent triple reuptake inhibitor.

In the current study, to support the safety of LPM570065 as a new potent triple reuptake inhibitors (TRIs), LPM570065 was investigated through a single- and 13-week repeated-dose oral toxicity evaluation and mutagenicity assays. In an acute toxicity evaluation, Sprague-Dawley (SD) rats were single administration at dose of 500, 1000 and 2000 mg/kg. The results suggested that two (2/20) and seven (7/20) animals were died in the 1000 and 2000 mg/kg group, respectively. In contrast, there were no treatment-related effects at a dose of 500 mg/kg. In a 13-week toxicity evaluation, SD rats were given 30, 100, or 300 mg/kg LPM570065 for 13 successive weeks and then allowed a 4-week recovery period. Impermanent salivation was found at each of the doses, and an impermanent minor body weight decrease was noted in the 300 mg/kg males (P < 0.05). Notably, serum prolactin levels were lowered by 43.25% and 78.65% in the male rats in 100 and 300 mg/kg groups, respectively (P < 0.05). Further, the serum testosterone was elevated by 37% in the 30 and 100 mg/kg males. In conclusion, the maximum tolerated dose (MTD) was 500 mg/kg and the lethal dose was 1000 mg/kg in SD rats after a single administration of LPM570065. In 13-week repeated-dose oral toxicity, the no-observed-adverse-effect level (NOAEL) of LPM570065 was greater than 300 mg/kg for rats. Moreover, LPM570065 was not mutagenic or clastogenic. According to this result it can be concluded that the MTD of LMP570065 is approximately up to 3000 mg/person/day in clinic, and the effects of LMP570065 on sexual function also should be considered.
(Copyright © 2018 Elsevier Inc. All rights reserved.)