Hypothetical framework for enhanced renal tubular secretion of drugs in cystic fibrosis

Several clinical studies demonstrate reduced serum concentrations of renall y excreted drugs in patients with cystic fibrosis (CF). To explain this phe nomenon, we propose a model supporting increased proximal tubular secretion of certain drugs in individuals with CF. We hypothesize that the chloride channel located on the apical surface of renal proximal tubular cells and c ontrolled by the cystic fibrosis transmembrane conductance regulator (CFTR) operates suboptimally in CF patients, and that the abnormal CFTR decreases Cl- reabsorption, resulting in an increased concentration of Cl- in the tu bular lumen. We postulate that, in an effort to maintain homeostasis, lumin al Cl- moves intracellularly in exchange for organic anions. The result of stimulating this anion exchanger is an increased rate of organic anion secr etion by the renal tubule. Hence, due to enhanced tubular secretion, indivi duals with CF demonstrate increased tubular clearance of organic anion drug s, resulting in lower steady state serum concentrations.