Chronic kidney disease (CKD) generally impacts clearance of renally
eliminated drugs but growing evidence shows that it can influence clearance of hepatically
eliminated drugs and a complete mechanistic understanding of this phenomenon
is still lacking. CKD leads to accumulation of uremic toxins, including indoxyl-
3-sulfate (3-INDS) and indole-3-acetic acid (3-IAA).
Objective: In this study, we evaluated the potential of 3-INDS and 3-IAA (10, 30
and 100 μM) to induce liver cytochrome P450 (CYP) enzymes CYP1A2, 2B6 and
3A4/5 using cultured primary human hepatocytes following once daily treatment for
Results: 3-INDS potently induced CYP1A2 mRNA and enzyme activity in a dose-dependent manner
but did not induce CYP2B6 or 3A4. At 100 μM, a concentration observed in humans under uremic conditions,
3-INDS increased CYP1A2 mRNA and activity by 93% and 292% respectively when compared
with prototypical inducer omeprazole. However, 3-IAA did not induce CYP1A2, 2B6 or 3A4.
Conclusion: These results suggest that the uremic toxin, 3-INDS, is a potent CYP1A2 inducer and
lends valuable mechanistic basis for how kidney disease can affect hepatic metabolism.