Influence of Anesthetic Regimens on the Intestinal Absorption of 5-Fluorouracil in Rats

Abstract

We investigated the influence of anesthetic regimens on the intestinal absorption of 5-fluorouracil (5-FU), which is known to be absorbed by concurrent Na⁺-dependent, carrier-mediated transport and passive transport, in single-pass perfusion experiments in rats. Compared with the absorption in unanesthetized rats, the regular dose of urethane (1.13g/kg) reduced the maximum transport rate (J_max), the Michaelis constant (K_m) and the membrane permeability coefficient of passive transport (P_{m, d}); a low dose of urethane (0.7g/kg) reduced J_max and K_m, but did not affect P_{m, d}; pentobarbital sodium (50mg/kg) increased J<max> without affecting K_m, and reduced P_{m, d}. The reductions in J_max and K_m were comparable for the regular and low doses of urethane. Thus, urethane and pentobarbital, which have been most commonly used in laboratory animal experiments, exerted qualitatively different effects on the carrier-mediated transport of 5-FU, although they similarly inhibited the passive transport. For urethane, the effect on the passive transport was avoided by reducing the dose, but the effect on the carrier-mediated transport was not. This influence of anesthetic regimens on intestinal drug absorption may not be easily scaled for normalizing absorption data. When compiling them for such purposes as establishing in situ-in vivo quantitative correlation, the absorption data in perfusion (in situ) should be categorized on the basis of anesthetic regimens, to avoid ending up with poor outcomes. We also examined the effect of urethane on the exsorption of Na⁺ in the intestinal loop where Na⁺-free buffer was introduced, and found a minimal effect. Therefore, urethane may not significantly affect Na⁺ concentration at the intestinal surface, ruling out the possibility of its indirect effect on the carrier-mediated transport of 5-FU through a reduction in the Na⁺ concentration. Urethane may directly affect the carrier and/or membrane environment.