Probing the Structure and Function of the Liver with the Multiple-Indicator Dilution Technique

Abstract

The liver is the most important drug eliminating organ that is capable of both metabolism and excretion. The efficiency with which the liver removes a drug is often expressed as the hepatic drug clearance, or the volume of perfusing fluid cleared of its contained drug per unit time. Clearance is affected by the hepatic blood flow rate, the binding to vascular proteins, transport across the sinusoidal membrane, and the K _m and V _max of the metabolic and excretory pathways (for reviews, see Gillette and Pang, 1977; Pang and Xu, 1988; Pang et al., 1991a; Goresky et al., 1993a, 1993b). The liver is a highly specialized and complex organ (Rappaport, 1958, 1980; Novikoff, 1959; Miller et al., 1979; de Leeue and Knook, 1984; Gooding et al., 1978; Jungerman and Katz 1982), and its attendant heterogeneities—capillary transit times (Goresky, 1963; Sherman et al., 1990; Almond and Wheatley, 1992; Pang et al., 1994a), transport (Burger et al., 1989; McFarlane et al., 1990), enzyme 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), acinar biliary excretion (Gumucio et al., 1978; Boyer et al., 1979), cosubstrate abundance (Smith et al., 1979; Murray et al., 1986; Chiba and Pang, 1995), and intracellular binding (Braakman et al., 1989; Bass et al., 1989)—must be viewed in an integrative fashion in order to accurately relate the intrahepatic events involved in drug and metabolite processing (Pang and Stillwell, 1983; Goresky and Groom, 1984; Goresky et al., 1994; Pang and Xu, 1988). The overall removal process is highly dependent on these variables as well as the concentration of drug entering the liver.