Anwer M S, Hegner D
J Pharmacol Exp Ther. 1983 May;225(2):284-90.
The effect of local anesthetics, dibucaine and procaine, on hepatic bile formation was studied in the isolated perfused rat liver. Perfusate Na+ and Cl- were replaced by other ions to define the possible mechanism of action. A single dose (50 mumol) of dibucaine produced an initial cholestasis followed by choleresis. Whereas dibucaine produced only choleresis at a lower dose (10 mumol), only the cholestatic effect was seen at a higher dose (100 mumol). Procaine, on the other hand, produced only choleresis at all doses (1, 10 and 100 mumol); this choleresis was associated with biliary secretion of procaine and its metabolites. Neither dibucaine nor procaine affected the low endogenous bile acid secretion in these studies. The diffusion permeability coefficient of [carboxy-14C]inulin was not altered significantly by dibucaine and procaine, suggesting no significant alteration of biliary permeability. Biliary secretion of Na+ or Cl- declined during cholestasis and increased during choleresis. The initial cholestatic effect of dibucaine was still present when perfusates Na+ and Cl- were replaced by permeable Li+ or NO3-, but declined when Cl- was replaced by relatively impermeable isethionate, suggesting a nonspecific effect. The choleretic effect of both dibucaine and procaine, however, declined significantly when Na+ or Cl- was replaced by Li+, NO3- or isethionate-. These ion-substitutions did not affect significantly the biliary secretion of procaine and its metabolites. The ability to induce biliary secretion of Na+ and Cl- also decreased when Cl- was replaced by NO3- or isethionate and when Na+ was replaced by Li+, respectively. These results suggest that a part of the choleretic effect of both dibucaine and procaine is specifically dependent on Na+ and Cl-. This fraction is thus unlikely to be due to the osmotic effect of the secreted drug. Further studies showed that dibucaine inhibited Na+-dependent hepatic uptake of taurocholate, suggesting possible interference with other Na+-dependent transport processes. It is proposed that although a part of the choleresis is due to the osmotic effect of the secreted drug, the specific dependency of a portion of the choleretic effect on Na+ and Cl- is due to inhibition of Na+-coupled Cl- reabsorption from the canaliculi.
在离体灌注大鼠肝脏中研究了局部麻醉药丁卡因和普鲁卡因对肝胆汁生成的影响。用其他离子替代灌注液中的Na⁺和Cl⁻以确定可能的作用机制。单剂量（50 μmol）的丁卡因产生了最初的胆汁淤积，随后是胆汁分泌增多。而丁卡因在较低剂量（10 μmol）时仅产生胆汁分泌增多，在较高剂量（100 μmol）时仅观察到胆汁淤积作用。另一方面，普鲁卡因在所有剂量（1、10和100 μmol）下均仅产生胆汁分泌增多；这种胆汁分泌增多与普鲁卡因及其代谢产物的胆汁分泌有关。在这些研究中，丁卡因和普鲁卡因均未影响内源性胆汁酸的低分泌。丁卡因和普鲁卡因对[羧基-¹⁴C]菊粉的扩散渗透系数没有显著改变，表明胆汁通透性没有显著改变。胆汁淤积期间Na⁺或Cl⁻的胆汁分泌减少，胆汁分泌增多期间增加。当灌注液中的Na⁺和Cl⁻被可渗透的Li⁺或NO₃⁻替代时，丁卡因最初的胆汁淤积作用仍然存在，但当Cl⁻被相对不可渗透的羟乙磺酸盐替代时则减弱，提示存在非特异性作用。然而，当Na⁺或Cl⁻被Li⁺、NO₃⁻或羟乙磺酸盐⁻替代时，丁卡因和普鲁卡因的胆汁分泌增多作用均显著减弱。这些离子替代对普鲁卡因及其代谢产物的胆汁分泌没有显著影响。当Cl⁻被NO₃⁻或羟乙磺酸盐替代以及当Na⁺被Li⁺替代时，诱导Na⁺和Cl⁻胆汁分泌的能力也分别下降。这些结果表明，丁卡因和普鲁卡因的部分胆汁分泌增多作用特别依赖于Na⁺和Cl⁻。因此，这一部分作用不太可能是由于分泌药物的渗透作用。进一步的研究表明，丁卡因抑制牛磺胆酸盐依赖Na⁺的肝脏摄取，提示可能干扰其他依赖Na⁺的转运过程。有人提出，虽然部分胆汁分泌增多是由于分泌药物的渗透作用，但部分胆汁分泌增多作用对Na⁺和Cl⁻的特异性依赖是由于抑制了小管中Na⁺偶联的Cl⁻重吸收。
