Can the enhanced renal clearance of antibiotics in cystic fibrosis patients be explained by P-glycoprotein transport?

摘要

PURPOSE: To investigate in vitro if P-glycoprotein (P-gp) transport can differentiate between antibiotic drugs exhibiting increased active renal clearance (CL(r)) in cystic fibrosis (CF) patients (i.e., dicloxacillin, trimethoprim) and drugs that do not exhibit this phenomenon (i.e.. cefsulodin, sulfamethoxazole). METHODS: Transport studies were carried out in MDCK (wild type) and MDR1-MDCK (P-gp overexpressing) cells that were grown to confluence on Transwell inserts. [14C]-mannitol transport and transepithelial electrical resistance (TEER) were measured to validate the integrity of the cells. Drug concentrations were analyzed using HPLC. RESULTS: Dicloxacillin and trimethoprim are substrates of P-gp (B-->A/A-->B ratios in MDR1-MDCK cells are 32 and 50, respectively). P-gp inhibitors (i.e., GG918, cyclosporine, ketoconazole, vinblastine) decreased the B-->A transport of dicloxacillin and trimethoprim and increased the A-->B transport of trimethoprim while non-P-gp inhibitors (e.g., PAH) had no effect. In contrast, cefsulodin and sulfamethoxazole are not substrates of P-gp (B-->sA/A-->B values in MDCK and MDR1-MDCK cells are -1). CONCLUSIONS: Our in vitro studies suggest that P-glycoprotein may play a role in increasing renal clearance of drug substrates in CF patients. Dicloxacillin and trimethoprim. which are both substrates of P-gp, show increased active renal clearance in CF patients while cefsulodin and sulfamethoxazole, which are not P-gp substrates, do not show increased active renal clearance in CF patients.