We performed experiments in anesthetized piglets with two cholesterol gallstone solvents, methyl tertbutyl ether and ethyl propionate, to determine whether blood levels of either solvent would increase during gallbladder instillation of these solvents under conditions simulating gallstone dissolution. The solvent was oscillated rapidly in and out of the gallbladder with a computer-controlled syringe pump; intraluminal pressure was set below the leakage pressure, and oscillating volume was set below the leakage volume to decrease loss of solvent into the intestine. Blood levels were measured with gas chromatography. Six piglets received methyl tert-butyl ether, and six piglets received ethyl propionate. During 2 hr of instillation with methyl tert-butyl ether, blood levels increased steadily to concentrations averaging 0.3 ml/L blood at 2 hr; during a 6-hr period of instillation, blood levels rose to above 0.4 ml/L blood. Replacement of methyl tert-butyl ether with saline solution in the gallbladder caused blood levels to decline gradually; plasma levels decreased by half in 90 min. In contrast, when ethyl propionate was infused for 2 or 6 hr, blood levels remained below the detection limit, probably because of high first-pass hepatic extraction. We conclude that, under conditions simulating those likely present in patients undergoing contact dissolution of gallbladder stones, the two solvents differ: Ethyl propionate is removed so rapidly from blood that its levels remain undetectable, whereas methyl tert-butyl ether levels in blood (and, presumably, peripheral tissues) increase continuously. If the absorption from the gallbladder and subsequent metabolism of ethyl propionate and methyl tert-butyl ether in human beings are similar to those of the piglet, side effects attributable to increased blood levels will be fewer if ethyl propionate is used than if methyl tert-butyl ether is used for contact dissolution of cholesterol gallstones. (HEPATOLOGY 1993;18:373–379).