Effect of route of administration on drug disposition

While the first-pass effect is a fairly generally understood phenomenon in the gross sense, it is not commonly appreciated that the rate at which the drug is delivered to the liver can influence the fraction of the administered dose which reaches the fluids of distribution. The drug molecules being absorbed via the hepatic portal vein intermix with previously absorbed drug recycling in the hepatic artery. The concentration of the drug returning via the hepatic artery is affected by the volume of distribution of the drug into body tissues (and the relative partition of the drug between the blood and the tissues). If one presumes that liver uptake is controlled by a Michaelis-Menten process of metabolism, it can be readily shown that the extent of extraction of the drug by the liver is controlled not only by the Michaelis-Menten constants, but also by the concentration of the drug transitting the liver per unit time. The effects of dose, rate of absorption, partitioning, and tissue distribution characteristics are systematically discussed and referred to in relation to selected examples of drugs in common use.The work reported here was supported in part by grant NIGMS16496-05.Presented by S. Reigelman at the Conference on Pharmacology and Pharmacokinetics: Problems and Perspectives, October 30–November 1, 1972, at the Fogarty International Center, National Institutes of Health, Bethesda, Maryland. This paper, in a slightly different format, will be published in the Proceedings of the Conference by Plenum Press, New York.