Propantheline

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

propantheline

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

Propantheline bromide a drug used for the treatment of peptic ulcers, was /evaluated/ in male and female Fischer 344/N rats and B6C3F1 mice for subchronic toxicity. The drug was admin in the feed for 13 wk at 0, 220,670, 2000, 6000 and 24,000 ppm in both species. /The cmpd/ caused a decr in weight gain at 24,000 ppm in male and female rats and at 6000 and 24,000 ppm in male and female mice. All rats survived treatment. The top dose of 24,000 ppm was fatal. Clinical signs of toxicity (dilated pupils and decr gastrointestinal emptying, similar to the atropine effects ... /observed/ in man, were seen in male and female rats at 24,000 ppm. Hyperplasia of the transitional epithelium of the urinary bladder was seen in high dose male rats and the end of 13 wk. /Propantheline bromide/

Propantheline bromide (PB) ... was tested for its effects on reproduction & fertility in CD-1 mice using the RACB protocol. Data on food & water consumption, body weights, & clinical signs during a 2 wk dose-range-finding study (Task 1) were used to set exposure concns for the Task 2 continuous cohabitation study at 0.0, 0.05, 0.16, & 0.5% in feed. Based on mean body weight & avg feed consumption data, the estimated daily doses were 71, 235, & 760 mg/kg bw. In the F0 animals, there were no deaths during Task 2. Body weight gain for the top dose males was reduced by a factor of 4, compared to controls. There was a statistically significant, but small (6%) reduction in the number of litters/pair at the top dose. The only other changes in reproductive indices for the F0 pairs occurred at the high dose level, & were a reduction in the mean weight of F1 pups adjusted for litter size at the top dose, by 4%, & an incr in the length of time to deliver each litter. This delay was greatest for the first 3 litters, while the difference was less for the last 2 litters. These modest reproductive effects (6% decr in litters/pair, & 4% decr in adjusted live pup weight) were considered too small to be detectable in the single litter generated by the Task 3 crossover, so Task 3 was not conducted. There were no adverse effects of PB consumption on the growth or viability of the F1 offspring in the last litter that was reared for second generation testing. After weaning the F2 mice, the F1 mice from control, middle & high dose groups were killed & necropsied. There were no weight changes or gross lesions noted in females, while male body weights were reduced by 11% at the top dose. There were no changes in sperm indices or in estrous cycle parameters. Only mice from the control & high dose groups were kept & treated with PB from weaning to the mating trial at /postnatal day/ 74 +/- 10. Compared to controls, the high dose PB mice had similar-sized litters, with the same proportion of live pups, & same sex ratio, but the adjusted live pup weight was reduced by 11%. After the delivery & evaluation of the F2 litters & estrous cycle data collection, the F1 adults were killed & necropsied. There was an 8% reduction in female body weight, & no change in organ weights. For males, body weight was reduced by 10%, & prostate weight was reduced by 25%. Epididymal sperm density was reduced at the high dose by 15%, while estrous cycle length & characteristics were unchanged. Thus, propantheline bromide caused detectable but small reductions in litter number, in both generations reduced adjusted pup weight, & reduced F1 prostate weight & sperm count. These effects were seen concomitant with male body weight changes but no other significant non-reproductive toxicities. /Propantheline bromide/

Approximately 70% of the dose is excreted in the urine, mostly as metabolites.

AFTER 95 HR HUMANS EXCRETED IN URINE 5% OF DOSE (0.03 G) OF PROPANTHELINE BROMIDE GIVEN ORALLY. /PROPANTHELINE BROMIDE, FROM TABLE/

The quarternary ammonium derivatives of the belladonna alkaloids are poorly absorbed after an oral dose; nevertheless, some of these compounds applied locally to the eye can cause mydriasis and cycloplegia. /Quarternary ammonium derivatives of belladonna alkaloids/