ORGAN CLEARANCE CONCEPTS - NEW PERSPECTIVES ON OLD PRINCIPLES

The removal capacity of an eliminating organ by metabolism and/or excr etion is often expressed as its clearance. Metabolic and excretory cle arances are considered to be mutually independent, and the sum of thes e constitute the whole organ clearance. The influence of metabolism on estimates of the excretory clearance and vice versa was examined for the liver and kidney with physiologically based models. Mass transfer first-order rate equations describing transport and removal were deriv ed Upon inversion of the matrices originating from the coefficients of these equations, the area under the curve (AUG) and clearance (dose/A UC) were obtained with the liver or kidney as the eliminating organ. A more complex solution was found to exist for the kidney since glomeru lar filtration, secretion; reabsorption, and intrarenal metabolism wer e present. To ascertain the effect of excretion on estimates of the me tabolic clearance as well as the effect of metabolism metabolism on es timates of the excretory clearance, intrinsic clearances for excretion or metabolism were set to zero. Clearance values were found to be alt ered when alternate pathways were present. Whereas excretory clearance estimates were consistently reduced in the presence of metabolism, me tabolic clearance estimates were affected differentially by excretion and varied according to the sire of metabolism. Excretion reduced meta bolic clearance estimates when metabolism occurred intracellularly. if metabolism occurred intraluminally (e.g., on the renal brush border o r luminal membrane), the metabolic clearance estimate could become hig her since the substrate was made available to the enzymes following it s excretion. As expected, these changes depended on the relative magni tudes of the intrinsic clearances for metabolism and excretion. The ab ove theory runs applied to the elimination of enalapril which is both metabolized and excreted by the perfused rat liver and kidney preparat ions. Data obtained in these studies were consistent with a set of pub lished physiologic parameters denoting transfer and intrinsic clearanc es. Perturbations on clearance estimates were studied by setting the m etabolic/excretory intrinsic clearance to zero, then to some finite va lue. In liver, the avid hepatocellular metabolism of enalapril reduced biliary clearance by 73%. For the kidney, the fractional excretion (F E or unbound excretory clearance/glomerular filtration rate) was decre ased modestly (from 0.64 to 0.44) with intracellular esterolysis, sis, whereas if metabolism had occurred intraluminally. FE would have been significantly decreased (from 1.8 to 0.45). Simulation results show c learly that clearance estimates are affected by the presence of altern ate removal pathways, and question the well-established principle that metabolic and excretory clearance estimates ave independent of each o ther.