The removal capacity of an eliminating organ by metabolism and/or excretion is often expressed as its clearance. Metabolic and excretory clearances are considered to be mutually independent, and the sum of these 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 derived. Upon inversion of the matrices originating from the coefficients of these equations, the area under the curve (AUC) and clearance (dose/AUC) were obtained with the liver or kidney as the eliminating organ. A more complex solution was found to exist for the kidney since glomerular filtration, secretion; reabsorption, and intrarenal metabolism were present. To ascertain the effect of excretion on estimates of the metabolic clearance as well as the effect of metabolism on estimates of the excretory clearance, intrinsic clearances for excretion or metabolism were set to zero. Clearance values were found to be altered when alternate pathways were present. Whereas excretory clearance estimates were consistently reduced in the presence of metabolism, metabolic clearance estimates were affected differentially by excretion and varied according to the site of metabolism. Excretion reduced metabolic clearance estimates when metabolism occurred intracellularly. If metabolism occurred intraluminally (e.g., on the renal brush border or luminal membrane), the metabolic clearance estimate could become higher since the substrate was made available to the enzymes following its excretion. As expected, these changes depended on the relative magnitudes of the intrinsic clearances for metabolism and excretion. The above theory was applied to the elimination of enalapril which is both metabolized and excreted by the perfused rat liver and kidney preparations. Data obtained in these studies were consistent with a set of published physiologic parameters denoting transfer and intrinsic clearances. Perturbations on clearance estimates were studied by setting the metabolic/excretory intrinsic clearance to zero, then to some finite value. In liver, the avid hepatocellular metabolism of enalapril reduced biliary clearance by 73%. For the kidney, the fractional excretion (FE or unbound excretory clearance/glomerular filtration rate) was decreased modestly (from 0.64 to 0.44) with intracellular esterolysis, whereas if metabolism had occurred intraluminally, FE would have been significantly decreased (from 1.8 to 0.45). Simulation results show clearly that clearance estimates are affected by the presence of alternate removal pathways, and question the well-established principle the metabolic and excretory clearance estimates are independent of each other.