Physiologically Based Pharmacokinetic Model of the Metabolism of Trichloroethylene by an Isolated Ventilated Perfused Lung

Abstract

Biotransformation is often a determinant of pharmacokinetic behavior and toxicity. While the liver is usually the quantitatively most significant site, metabolism in other tissues may cause nonhepatic toxicity and also may affect the pharmacokinetic behavior of chemicals. In these cases, structural models of pharmacokinetic and pharmaco-dynamic processes can explicitly describe the nonhepatic metabolism. As a first step in development of such models for a series of volatile halogenated toxicants, a “physiologically realistic” isolated, ventilated perfused lung (IVPL) was used to quantify the pulmonary metabolism of trichloroethylene (TCE). Concurrent with laboratory studies, a mathematical, structurally based model of the IVPL was developed and used in computer simulations. These simulations were used for refinement of the IVPL design, estimation of pulmonary V_max and K_m for TCE from metabolite data, and estimation of pulmonary first-pass metabolic clearance. The V_max and K_m estimates were obtained from male, Fischer 344 (F-344) rat lungs exposed to 50–400 ppm TCE using both blood and artificial perfusates. The TCE metabolism was quantified from the appearance of trichloroethanol in perfusate. With blood perfusate, the pulmonary V_max for TCE was 0.077 mg/(kg.h) with K_m - 0.25 mg TCE/l, With artificial perfusate, the V_max was 0.037 mg4kg.h) with K, - 0.80 mg/l. These parameters represent, respectively, 0.0016–0.0034 of whole-body V_max for TCE. Computer simulation indicated that the F-344 rat lung does not have a significant first-pass clearance capability for inhaled TCE (less than 7%). In summary, this study indicated that the male F-344 rat lung accounts for a very small fraction of total in vivo metabolism of TCE.