Dr. Huet is a Chercheur-Boursier of the Ministere des Affaires Sociales du Quebec, and Dr. Villeneuve is a Scholar of the Canadian Liver Foundation
Determinants of Drug Disposition in Patients with Cirrhosis†
Article first published online: 21 SEP 2007
Copyright © 1983 American Association for the Study of Liver Diseases
Volume 3, Issue 6, pages 913–918, 1983
How to Cite
Huet, P.-M. and Villeneuve, J.-P. (1983), Determinants of Drug Disposition in Patients with Cirrhosis. Hepatology, 3: 913–918. doi: 10.1002/hep.1840030604
Part of this work was presented at the 32nd Annual Meeting of the American Association for the Study of Liver Diseases in Chicago (1981) and appeared in abstract form (28D).
- Issue published online: 21 SEP 2007
- Article first published online: 21 SEP 2007
- Manuscript Accepted: 4 JUN 1983
- Manuscript Received: 10 FEB 1983
- Medical Research Council of Canada
- The Canadian Liver Foundation
The effects of alterations of the hepatic blood flow, the intrinsic clearance, and the anatomy of the portal circulation on drug disposition were investigated in 53 cirrhotic patients with portal hypertension using indocyanine green (ICG) and lidocaine as model drugs. ICG disposition was studied by sampling from an artery and one hepatic vein following i.v. injection, with determination of systemic and intrinsic clearances and hepatic blood flow. Lidocaine disposition was studied following i.v. and oral administration from peripheral vein disappearance curves, with determination of systemic and intrinsic clearances and systemic availability. The shunted fraction of intestinal blood flow (f) was measured from the combined ICG and lidocaine disposition studies. In the 53 patients, systemic clearances of ICG and lidocaine varied widely and were significantly correlated with each other (r = 0.725, p < 0.001). The systemic clearances of both ICG and lidocaine were not related to hepatic blood flow but were significantly correlated to their respective intrinsic clearances (for ICG: r = 0.948, p < 0.001; for lidocaine: r = 0.873, p < 0.001). Lidocaine systemic availability was also found to vary widely from 0.2 to 1.0. In 28 patients, f was <0.1 indicating minimal extrahepatic shunting and in these patients, lidocaine systemic availability was related to its intrinsic clearance (r = –0.717, p < 0.001); in the 25 other patients with significant extrahepatic shunting (f > 0.1), the extent of lidocaine systemic availability was related to both intrinsic clearance (r = −0.819, p < 0.001) and extrahepatic shunting (r = 0.913, p < 0.001). It is concluded that, in patients with cirrhosis: (i) the disposition of drugs with intermediate-high hepatic extraction ratios is no longer influenced by hepatic blood flow but becomes limited by intrinsic clearance; and (ii) the decrease of intrinsic clearance plus extrahepatic shunting, when present, are responsible for the increased systemic availability of this type of drug.