Local and systemic effects of intraduodenal exposure to topical gallstone solvents ethyl propionate and methyl tert-butyl ether in the rabbit.
During topical dissolution of gallstones, solvent can escape to the duodenum causing toxic effects that have not yet been adequately quantified. We compared the local intestinal cytotoxic and systemic hepatotoxic effects of two gallstone solvents, methyl tert-butyl ether and ethyl propionate, on the rabbit's duodenum. Methyl tert-butyl ether, ethyl propionate, or saline (control) was infused intraduodenally for 3 hr in 32 male New Zealand rabbits. The solvents were infused either at a high infusion rate of 8.5 microl/min or at a low rate of 4.0 microl/min. Blood samples were collected for biochemical analysis from each animal before and after the 3-hr infusion period. A standardized histologic scoring system was used by a pathologist blinded to the treatments to quantify liver and intestinal tissue injury. None of the animals studied showed any significant changes in serum alkaline phosphatase, amylase, bilirubin, or their hepatic histology or histologic scoring for mucosal necrosis and ulceration. At the higher dose, methyl tert-butyl ether produced significantly more submucosal inflammation (P = 0.0017) and showed a trend of causing more submucosal edema than ethyl propionate, but ethyl propionate led to significantly higher elevations of aminotransferases than methyl tert-butyl ether as compared to saline. There were no detectable blood levels of methanol or ethanol in any of the animals studied. Ethyl propionate may be less damaging to the intestinal mucosa of the rabbit than methyl tert-butyl ether, but at the higher dose (equivalent to 60 ml/3 hr in a 70-kg human) it appears to produce more biochemical liver injury when administered intraduodenally.
Clerici
C
C
Institute of Gastroenterology and Digestive Endoscopy, University of Perugia, Italy.
Gentili
G
G
Zakko
S F
SF
Balò
S
S
Miglietti
M
M
Giansanti
M
M
Modesto
R
R
Guttermuth
C F
CF
Morelli
A
A
D000287:Administration, Topical; D000818:Animals; D002769:Cholelithiasis / Q000628:therapy*; D004386:Duodenum / Q000187:drug effects* / Q000473:pathology; D000431:Ethanol / Q000097:blood; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D000432:Methanol / Q000097:blood; D008738:Methyl Ethers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011422:Propionates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011817:Rabbits; D012997:Solvents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D013997:Time Factors
D008738:Methyl Ethers; D011422:Propionates; D012997:Solvents; C043243:methyl tert-butyl ether; D000431:Ethanol; C069373:ethyl propionate; D000432:Methanol