Investigating the role of P-glycoprotein on drugs exhibiting enhanced renal clearance in cystic fibrosis patients

The goal of the research was to determine if P-glycoprotein (P-gp) plays a role in enhancing the renal clearance (CLr) of drugs in cystic fibrosis (CF) patients. We hypothesized that the enhanced CLr of drugs observed in CF patients was due to increased P-gp expression in those patients, which would caused increased CLr of drugs that are substrates of P-gp. Bidirectional transport and inhibition study results in control (MDCK1) and P-gp overexpressing (MDCK1-MDR1) cell lines showed that antibiotics that have a higher active CLr in CF patients (dicloxacillin, trimethoprim and ciprofloxacin) are substrates of P-gp while those that do not (sulfamethoxazole, iothalamate and cefsulodin), are not substrates of P-gp. Ciprofloxacin, besides being a substrate of P-gp, is also a substrate of an unidentified absorptive transporter. In vivo pharmacokinetic studies showed no correlation between P-gp expression and the CLr of trimethoprim and ciprofloxacin in mice. GG918, a P-gp inhibitor, had no effect on the disposition of trimethoprim and ciprofloxacin in rats. There was 3-fold higher mdr1a and 14-fold higher mdr1b expression in the kidneys of female than male wild type mice. P-gp expression was similar between male and female ΔF508 CF mice. However, there was a difference in P-gp expression between wild type and ΔF508 CF mice. Both mdr1a and mdr1b expressions were decreased by approximately 60% and 70%, respectively, in female ΔF508 CF compared to female CF wild type mice. On the other hand, both the mdr1a and mdr1b expressions were increased by approximately 50% and 360%, respectively, in male ΔF508 CF compared to male CF wild type mice. The combined overall effect in the kidneys of male and female ΔF508 CF mice was a two-fold increase in mdr1b expression. This agrees with our hypothesis that P-gp expression might be increased in the kidneys of CF patients. There was no difference in the expression of cftr between the kidneys of P-gp wild type and P-gp knockout mice, regardless of the sex of the mice. We also compared the expression of MDR1 between CFPAC-1 and CFPAC-1 pLJ CFTR cells. In the presence of wild type CFTR gene, MDR1 expression was significantly decreased while the expressions of MRP1, 2 and 3 and OATP-C, D, E and 8 were not changed. This result agrees with the hypothesis that P-gp expression might be upregulated in the kidneys of CF patients due to defects in their CFTR gene. In conclusion, the cause of the enhanced CLr of drugs in CF patients remains unknown. More research will need to be performed to answer the question and in determining whether P-gp could be responsible for the observed enhanced CLr in CF patients.