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.