Nonrenal drug clearance in CKD: Searching for the path less traveled

Patients with chronic kidney disease (CKD) represent a significant and growing segment of the US population. A mounting body of experimental and clinical evidence indicates that nonrenal drug clearance is altered in patients with CKD. Specific nonrenal clearance (CL(NR)) pathways that are affected have been identified in experimental models, and include cytochrome P450 enzymes, P-glycoprotein, and organic anion-transporting polypeptides. Altered CL(NR) of several drugs has been described in clinical pharmacokinetics studies, but to date the specific CL(NR) pathways that are affected in CKD patients and result in clinically significant changes in drug exposure have not been definitively established, and the mechanism has not been elucidated. Accumulated uremic toxins may downregulate or directly inhibit drug metabolism and transport pathways, and may do so in a reversible manner. Future Food and Drug Administration recommendations pertaining to the conduct of pharmacokinetic studies in CKD will undoubtedly facilitate the search for the CL(NR) path less traveled, clarify the mechanisms involved, improve our understanding of the clinical significance of altered CL(NR) of individual drugs, and lead to more comprehensive drug dosing recommendations for patients with CKD. This review summarizes our current understanding of this field, focusing on recent developments in the search for the CL(NR) "path less traveled" in CKD.