Time-dependent modifications of splanchnic circulation in female pigs submitted to end-to-side portacaval anastomosis

Fractional systemic bioavailability of orally administered drugs was found to be unexpectedly low in liver cirrhosis, even after surgical portal-syste mic shunting. Fecal loss or intestinal first-pass elimination were assumed to explain the finding. In this paper we evaluated alternative pathophysiol ogical interpretations relating low bioavailability to adaptive circulatory modifications. (D)-Sorbitol was used because its hepatic extraction is ver y high and hepatic removal follows a flow-dependent clearance regimen. D-So rbitol bioavailability was measured at steady state in pigs submitted to en d-to-side portacaval anastomosis, immediately after surgery and four weeks later. Intestinal first-pass elimination dependent on fecal loss and intral uminal degradation was excluded by administering D-sorbitol into the superi or mesenteric artery. Almost complete bioavailability was observed immediat ely after surgery (N = 6, 0.96 +/- 0.08); four weeks later the bioavailabil ity dropped (-36.8 +/- 18.7%; P < 0.001) while hepatic clearance significan tly increased (+83.6 <plus/minus> 47.9%; P < 0.01). Experimental data suppo rt the hypothesis that adaptive circulatory changes spontaneously occur aft er some time, leading to a lower than expected portal bioavailability.