Effect of portacaval shunt on the disposition of drugs with and without first-pass effect

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 195; no. 3; pp. 416 - 423
• Main Authors: Gugler, R, Lain, P, Azarnoff, D L
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.12.1975
• Subjects: Animals; Antipyrine - metabolism; Biological Availability; Dogs; Female; Half-Life; Kinetics; Lidocaine - metabolism; Liver - metabolism; Male; Portacaval Shunt, Surgical; Salicylamides - metabolism; Time Factors
• ISSN: 0022-3565; 1521-0103

The pharmacokinetic parameters of lidocaine, antipyrine and salicylamide were studied in dogs before and after construction of a portacaval shunt. The systemic availability of antipyrine was not altered significantly by the surgical procedure whereas the availability of lidocaine and salicylamide, drugs with a marked first-pass effect, was increased from 14.8 +/- 2.8 to 81.3 +/- 5.2% and from 21.8 +/- 7.8 to 57.5 +/- 2.5%, respectively. Of the 78% first-pass extraction of salicylamide, 36% is due to hepatic extraction whereas the remaining 42% is accounted for by intestinal wall extraction. The presence of a portacaval shunt also reduced the plasma clearance of lidocaine and antipyrine, but not salicylamide. The apparent volume of distribution was decreased only with salicylamide. Surgical construction of a portacaval shunt in dogs in a good model to evaluate first-pass effect. Physicians should adjust downward the dose of drugs with a first-pass effect. Physicians should adjust downward the dose of drugs with a first-pass effect in patients with a surgical portacaval shunt or endogenous portal systemic shunts such as seen in cirrhosis of the liver.