Pharmacokinetic Modeling of Drug Conjugates

Abstract

The liver is the most important drug-eliminating organ that is capable of both conjugation and biliary excretion. Much has been reported on the liver’s role as a highly specialized and heterogeneous organ (Novikoff 1959; Miller et al. 1979; de Leeue and Knook 1984; Gooding et al. 1978; Jungerman and Katz 1982), and an accurate physiological description of hepatic drug conjugation and conjugate processing by the liver necessitates consideration of the structure of the liver and its microcirculation (Pang and Stillwell 1983; Goresky a n d Groom 1984; Pang 1990; Pang et al. 1991, 1992). The attendant heterogeneities — in enzymic zonation (Baron et al. 1982; Ullrich et al. 1984; Knapp et al. 1988; Thurman et al. 1987; Pang et al. 1983; Pang and Terrell 1981a), biliary excretion (Gumucio et al. 1978; Boyer et al. 1979), capillary transit times (Goresky 1963; Goresky and Groom 1984), cosubstrate abundance (Asgher et al. 1975; Smith et al. 1979; Murray et al. 1986), intracellular binding (Braakman et al. 1987, 1989; Bass et al. 1989) and transport (Burger et al. 1989; Mcfarlane et al. 1990), together with clearance modifiers, such as organ blood flow, drug and conjugate binding to vascular proteins, transmembrane clearance, and the K _max and V _max of the saturable eliminatory pathways (for reviews, see Goresky and Groom 1984; Pang a n d Xu 1988; Pang 1990; Pang et al. 1991, 1992; Goresky et al. 1993a,b) — must be viewed as a whole in order to accurately relate the occurrences involved during drug and conjugate processing within the liver.