The work investigates functional variability of hepatic arterial and portal venous streams in relation to drug availability. In an isolated rat liver system perfused in all experiments at a constant total flow of 10 ml X min-1, drug availability was found to be 18 and 3 times greater for lidocaine and meperidine, respectively, when infused through the hepatic artery compared to portal vein administration. When both hepatic artery and portal vein were perfused, drug availability increased log linearly for lidocaine, and linearly for meperidine with increasing hepatic artery flow contribution. Injection of 15-micron gamma-labeled microspheres into the hepatic artery and portal vein did not reveal arteriovenous or portovenous shunting channels greater than 15 micron in diameter. However, the ratios of the mean transit times of albumin and red blood cells were found to be significantly lower through the hepatic artery, indicating a possible reduction in perisinusoidal albumin space. When both hepatic artery and portal vein were perfused, linear correlations were obtained for values of this ratio plotted against increasing hepatic artery flow contributions. Data from the red blood cell transit time studies, as well as data on lidocaine availability, suggest the presence of functionally separate capillary beds for the hepatic arterial and venous streams.