Hypothetical framework for enhanced renal tubular secretion of drugs in cystic fibrosis.
Several clinical studies demonstrate reduced serum concentrations of renally excreted drugs in patients with cystic fibrosis (CF). To explain this phenomenon, 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 controlled 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 tubular lumen. We postulate that, in an effort to maintain homeostasis, luminal Cl- moves intracellularly in exchange for organic anions. The result of stimulating this anion exchanger is an increased rate of organic anion secretion by the renal tubule. Hence, due to enhanced tubular secretion, individuals with CF demonstrate increased tubular clearance of organic anion drugs, resulting in lower steady state serum concentrations.
Woodland
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C
The Research Institute, The Hospital for Sick Children, Department of Pediatrics, The University of Toronto, Ontario, Canada.
Blowey
D
D
Ito
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S
Spino
M
M
Koren
G
G
D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D006801:Humans; D017136:Ion Transport; D007684:Kidney Tubules / Q000378:metabolism*; D008954:Models, Biological; D010599:Pharmacokinetics
C505032:CFTR protein, human; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator