Effects of Chronic Kidney Disease on Drug Disposition: Transport, Metabolism, and Pharmacokinetics of Different Biopharmaceutics Drug Disposition Classification System (BDDCS) Drugs

Pharmacokinetic changes of non-renally excreted drugs have been observed in chronic kidney disease (CKD) patients. Typically, dose adjustment is implemented in CKD patients for drugs that are renally excreted, but not for non-renally excreted drugs. I hypothesized that uremic toxins in CKD patients alter the transport of drugs and consequently alter drug disposition. Since BDDCS categorize drugs based on drug transporter involvement for drug disposition, I also hypothesized that BDDCS can be used as a tool to predict which drugs (Class 2, 3, and 4 but not Class 1) would have changes in drug disposition in CKD patients. Uremic toxins in CKD may alter drug metabolism; however, uremic toxins have not been investigated for their effect on drug transporters. In this thesis I investigated if uremic toxins affect drug transport in tranfected cells (transfected with human hepatic transporters), and rat and human hepatocytes. I observed no change in drug transport for the Class 1 drug propranolol, but reduction in transport for Class 2 losartan and Class 4 eprosartan in transfected cells. On the other hand, in rat and human hepatocytes, changes were only observed for losartan. There was no change in metabolism in rat or human microsomes for propranolol or losartan in the presence of hemodialysis (HD) serum. Studies have shown that hepatic transporters play an important role in drug disposition, but changes in hepatic drug transporters in CKD have not been explored. I used a rat model chronic kidney disease and investigated the hepatic drug disposition of propranolol, losartan, and eprosartan in the isolated perfused rat liver system by perfusing the liver with HD serum or normal serum. The results from these studies were inconclusive, the variability was high and the number of animals used was small. A human clinical study was carried out in CKD patients and healthy volunteers. I investigated the pharmacokinetic changes of propranolol, losartan, and erythromycin. As predicted there were no changes in propranolol PK, but there were significant changes for losartan metabolite and erythromycin. This showed that BDDCS can be a useful tool for predicting changes in drug disposition in CKD patients