Drug Exposure in Chronic Kidney Disease: It Is Not Just About the Glomerular Filtration Rate

Chronic kidney disease (CKD) affects over 10% of the world's population and is associated with high morbidity and mortality rates. The management of CKD is complex; CKD alters drug pharmacokinetics and pharmacodynamics and further complicates therapeutic strategies regimens. Uremic toxins accumulate in patients with CKD and significantly impact drug pharmacokinetics and drug responses. These toxins modify drug pharmacokinetics. Indeed, uremic toxins can alter intestinal absorption by affecting drug transporters, such as P-glycoprotein and multidrug resistance-associated proteins. These changes modify the bioavailability of drugs and change drug absorption profiles in patients with CKD. Furthermore, uremic toxins interfere with drug distribution and metabolism. For instance, the urea-driven carbamylation of albumin can reduce drug-binding sites on this plasma protein and thus increase the free drug fraction. In the liver, CKD can reduce the expression of cytochrome P450 enzymes and thus impair drug biotransformation. Furthermore, uremic toxins can interact with cellular transporters, affecting drug clearance and leading to drug accumulation. In terms of pharmacodynamics, uremic toxins can alter receptor function and impair drug effectiveness. The blood-brain barrier may also be disrupted by the accumulation of toxins; this enhances drug penetration into the brain and increases the risk of adverse effects. After providing a brief summary of the various drug elimination pathways and the definitions and classification of uremic toxins, we shall use examples to illustrate the potential impact of a decrease in glomerular filtration rate (GFR) and/or an increase in uremic toxin levels on drug pharmacokinetics and pharmacodynamics.