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-systemic shunting. Fecal loss or intestinal first-pass elimination were assumed to explain the finding. In this paper we evaluated alternative pathophysiological interpretations relating low bioavailability to adaptive circulatory modifications. D-Sorbitol was used because its hepatic extraction is very high and hepatic removal follows a flow-dependent clearance regimen. D-Sorbitol bioavailability was measured at steady state in pigs submitted to end-to-side portacaval anastomosis, immediately after surgery and four weeks later. Intestinal first-pass elimination dependent on fecal loss and intraluminal degradation was excluded by administering D-sorbitol into the superior mesenteric artery. Almost complete bioavailability was observed immediately after surgery (N = 6, 0.96+/-0.08); four weeks later the bioavailability dropped (-36.8+/-18.7%; P < 0.001) while hepatic clearance significantly increased (+83.6+/-47.9%; P < 0.01). Experimental data support the hypothesis that adaptive circulatory changes spontaneously occur after some time, leading to a lower than expected portal bioavailability.
Molino
G
G
Divisione di Medicina Generale A, A.O. San Giovanni Battista, Turin, Italy.
Avagnina
P
P
Garrone
C
C
Sansoè
G
G
Degerfeld
M M
MM
Peretti
P
P
Tinivella
M
M
Bianco
S
S
D000818:Animals; D001682:Biological Availability; D005260:Female; D011167:Portacaval Shunt, Surgical; D013012:Sorbitol / Q000493:pharmacokinetics; D013152:Splanchnic Circulation / Q000502:physiology*; D013552:Swine
D013012:Sorbitol