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An Evaluation of the Venous Equilibrium Model for Hepatic Clearance using Isolated Perfused Rainbow Trout Livers
Citation:
HOFFMAN, A. D., T. L. TER LAAK, P. N. FITZSIMMONS, AND J. W. NICHOLS. An Evaluation of the Venous Equilibrium Model for Hepatic Clearance using Isolated Perfused Rainbow Trout Livers. Presented at SOT Annual Meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
The venous equilibrium model is widely used to describe hepatic clearance (CLH) of chemicals metabolized by the liver. If chemical delivery to the tissue does not limit CLH, this model predicts that CLH will approximately equal the product of intrinsic metabolic clearance and a term (fu ) that describes the free chemical concentration in plasma (or in the case of isolated perfused livers, the perfusion buffer). Despite its general acceptance, however, experimental efforts to validate the model have provided contradictory results, particularly for compounds that are highly bound or are substrates for specific transport proteins. These efforts have been further complicated by the challenge of measuring fu accurately. In this study we evaluated the venous equilibrium model by perfusing isolated trout livers with four polyaromatic hydrocarbons (PAHs): naphthalene, fluoranthrene, phenanthrene, and anthracene (log Kow 3.7 to 4.8). The effect of fu on CLH was studied by manipulating the concentration of bovine serum albumin in the perfusion buffer using an experimental design wherein each liver acted as its own control. Free chemical concentrations afferent and efferent to the liver were measured using solid phase microextraction (SPME) fibers. Additional SPME fibers were implanted into the tissue itself. Fluoranthene, phenanthrene, and anthracene were extensively metabolized resulting in extraction fractions (E) ranging from 25 to 75%. Naphthalene was less well metabolized (E < 25%). Preliminary findings provide support for the venous equilibrium model; for each of the three highly metabolized PAHs, an increase in fu resulted in a roughly proportional increase in CLH. Free chemical concentrations within the tissue were also found to be close to those in buffer samples efferent to the liver. Ongoing work is designed to characterize the quantitative relationship between fu and CLH.
Description:
The venous equilibrium model is widely used to describe hepatic clearance (CLH) of chemicals metabolized by the liver. If chemical delivery to the tissue does not limit CLH, this model predicts that CLH will approximately equal the product of intrinsic metabolic clearance and a term (fu ) that describes the free chemical concentration in plasma (or in the case of isolated perfused livers, the perfusion buffer). Despite its general acceptance, however, experimental efforts to validate the model have provided contradictory results, particularly for compounds that are highly bound or are substrates for specific transport proteins. These efforts have been further complicated by the challenge of measuring fu accurately. In this study we evaluated the venous equilibrium model by perfusing isolated trout livers with four polyaromatic hydrocarbons (PAHs): naphthalene, fluoranthrene, phenanthrene, and anthracene (log Kow 3.7 to 4.8). The effect of fu on CLH was studied by manipulating the concentration of bovine serum albumin in the perfusion buffer using an experimental design wherein each liver acted as its own control. Free chemical concentrations afferent and efferent to the liver were measured using solid phase microextraction (SPME) fibers. Additional SPME fibers were implanted into the tissue itself. Fluoranthene, phenanthrene, and anthracene were extensively metabolized resulting in extraction fractions (E) ranging from 25 to 75%. Naphthalene was less well metabolized (E < 25%). Preliminary findings provide support for the venous equilibrium model; for each of the three highly metabolized PAHs, an increase in fu resulted in a roughly proportional increase in CLH. Free chemical concentrations within the tissue were also found to be close to those in buffer samples efferent to the liver. Ongoing work is designed to characterize the quantitative relationship between fu and CLH.