DRUG-INTERACTIONS AT THE RENAL LEVEL - IMPLICATIONS FOR DRUG DEVELOPMENT

The kidney plays a major role in the elimination of drugs. The purpose of this paper is to: (i) review the mechanisms of renal elimination ( ii) identify potential mechanisms for renal drug interactions; (iii) r eview in vitro and in vivo animal models for studying renal eliminatio n mechanisms and identifying potential drug-drug interactions; (iv) re view experimental designs used in identifying drug-drug interactions i n humans with an emphasis on gaining information regarding the mechani sm of the interaction; and (v) make recommendations regarding the pote ntial for renal drug interactions in drug development. It is concluded that clinically significant drug interactions resulting in toxicity b ecause of some mechanism at the renal level appear to be relatively ra re and that in vitro screening should not be done on all drugs during drug development. Five potential mechanisms exist for drug interaction s at the renal level: (i) a displacement of bound drug resulting in an increase in drug excretion via an increase in glomerular filtration; (ii) competition at a tubular secretion site resulting in a decrease i n drug excretion; (iii) competition at the tubular reabsorption site r esulting in an increase in drug excretion; (iv) a change in urinary pH and/or flow that may increase or decrease drug excretion depending on the pKa of the drug; and (v) inhibition of renal drug metabolism. The most well known renal drug interaction is competitive inhibition of t ubular secretion, ultimately leading to an increase in plasma drug con centration. Only when renal clearance is a major contributor to the to tal clearance (> 30%) and plasma concentrations are greater than the M ichaelis-Menten transport constant does the potential exist for clinic ally significant renal drug-drug interactions because only then does n onlinear pharmacokinetics become evident. The potential for drug inter actions is small when renal clearance is less than 20 to 30% of the to tal clearance and/or when plasma concentrations are less than the Mich aelis-Menten transport constant, unless the drug has a narrow therapeu tic window.