PHYSIOLOGICAL MODELING OF RENAL DRUG CLEARANCE

A physiological model of renal drug clearance is presented with the ai m of establishing a basis for adjusting drug dosing regimens in renal insufficiency. In agreement with the morphology of blood supply to the nephron, the model assumes serial arrangement of the processes involv ed in drug excretion. Fractional extraction by filtration in the glome ruli is defined in terms of the product of the unbound fraction of the drug, the filtration fraction being responsible for the limited extra ction efficiency of this process. For a description of the limitations of the tubular secretory process by plasma flow through peritubular c apillaries, the parallel tube model is utilized. The assumption of dir ect proportionality between the transport maximum of the secretory pro cess and filtrate flow in the tubules permits a quantitative compariso n of the intrinsic tubular secretion clearance and the effectiveness o f the filtration process. Provided that the secretory mechanism is hig hly effective, renal clearance becomes dependent only on kidney plasma flow and the fraction of drug not reabsorbed in the tubules. Tubular reabsorption results only in a proportional decrease in renal clearanc e. The model predicts proportionality of renal drug clearance to GFR, which as a rule is used for dosage adjustment of drugs in renal insuff iciency, only for compounds exclusively excreted by filtration. Compou nds also excreted by tubular secretion in general exhibit a curvilinea r relationship. The curvature is less pronounced as an increasing frac tion of the drug is protein bound in blood. Therefore, for dosage adju stment of drugs secreted in the tubules and highly bound in blood, pro portionality between renal clearance and GFR can serve as a reasonable approximation. According to the model, distinct deviations from simpl e proportionality, which will require dosage adjustment methods involv ing assessment both of glomerular and tubular functions of the kidney, can be expected mainly for drugs for which an efficient flow-dependen t secretion process is not counteracted by extensive binding of the dr ug to blood constituents.