Influence of Azathioprine on Hepatic Reserve in Chronic Active Liver Disease

Abstract

Howard, 1967).Following the demonstration that hepatic uptake of ICG is a saturable process (Hunton, Bollman, and Hoffman, 1961), Paumgartner, Probst, Kraines, and Leevy (1970) utilized classical MichaelisMenten enzyme kinetics to determine the maximal rate of ICG removal (Rmax) from disappearance rates of multiple, submaximal doses. The discovery of a close correlation between regenerating liver mass in the rat and Rmax by Rikkers and Moody (1974a) encouraged the application of this technique to the clinical estimation of hepatic reserve.The purposes of the present investigation are twofold: (1) to determine if hepatic removal of ICG in patients with chronic active liver disease follows saturation kinetics, allowing calculation of Rmax, and (2) to assess the role of azathioprine in the management of these patients by evaluating the influence of this drug on Rmax.

Hepatic Elimination of Indocyanine Green with Special Reference to Distribution Kinetics and the Influence of Plasma Protein Binding

“…Saturation of hepatic ICG removal with estimates of V,,, and K, has been reported in studies on rats (Klaassen & Plaa 1969;Paumgartner & Reichen 1975;Scharschmidt et al 1975;Ohkubo et al 1978;Ott 1995), rabbits (Klaassen & Plaa 1969;Thiessen et al 1984), dogs (Hunton et al 1960; 30 I . Estimation of V,,, and K, for the uptake of ICG in the isolated perfused rat liver from male or female rats (Ott 1995 Klaassen & Plaa 1969) and humans (Moody et al 1974;Rikkers & Sherlock 1975;Martin et al 1976). Some authors report a toxic effect at high ICG concentrations that makes estimates of V,,, difficult (Klaassen & Plaa 1969;Thiessen et al 1984), as illustrated in Fig.…”

“…This test is still occasionally used (Yamanaka et al 1990;Sugimura et al 1994). Measurement of fractional plasma disappearance rate (k12) by one of these methods has been widely used (Cherrick et al 1960;Hunton et al 1960;Acocella et al 1965;Moody et al 1974;Rikkers & Sherlock 1975;Branch et al 1976;Ohkubo et al 1978;Kawasaki er al. 1988 Ikeda et al 1993;Ishigami et al 1993;Koneru et al 1993;Jalan et al 1994).…”

“…The curve of In(conc) versus time was supposed to be linear at all doses, but the initial uptake rate (dose times fractional clearance rate) was assumed to decline with dose in a Michaelis-Menten like fashion. This model has been used to estimate K, and V, , , for ICG uptake in man (Moody et al 1974;Martin et al 1975;Rikkers & Sherlock 1975;Martin et al 1976;Ohkubo et al 1978), rat (Klaassen & Plaa 1969;Paumgartner et al 1970;Scharschmidt et al 1975), rabbits (Klaassen & Plaa 1969) and dogs (Klaassen & Plaa 1969;Furuhama et al 1996). The method has important limitations.…”

“…It is difficult to administer sufficiently large doses to approach saturation, so the fitting to Michaelis-Menten kinetics depended on the initial, slightly curved part of the uptake rate versus dose curve. This was especially a problem in humans (Moody et al 1974;Martin et al 1975;Rikkers & Sherlock 1975;Martin et al 1976;Ohkubo et al 1978). The plasma disappearance curves were in fact not linear, but rather upward concave, so the fitted slope depended on the observation time.…”