Figure 3.

Drug clearance by metabolism can also decrease with declining kidney function. Drawn from data presented by Rowland Yeo et al. (45), the analyses are of clearance data in clinical studies after correcting for differences in protein binding and blood to plasma partitioning. The drugs were chosen as a probe of different CYP450s (theophylline for 1A2, rosiglitazone for 2C8, bosentan for 2C9, omeprazole for 2C19, bufuralol for 2D6, and midazolam for 3A4). Although these data are illustrative, the effect on expression and activity of some cytochrome P450 isoenzymes is controversial. For example, some studies have identified progressive reductions in clearance by CYP2D6 (46), whereas others have found no difference in enzyme activity in advanced CKD for CYP3A4/5 (16,46) and CYP2C9 (47). Instead, the changes in metabolic clearances noted in CKD may also relate to changes in expression or function of drug transporters (for example, those on the hepatocyte cell membrane). Additional studies in human subjects are required to further clarify the extent of any effect.