Assessment of hepatic cytochrome P450 3A activity using steroid metabolic markers in patients with renal impairment

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Background: The renal function of individuals is one of the reasons for the variations in therapeutic response to various drugs. Patients with renal impairment are often exposed to drug toxicity, even with drugs that are usually eliminated by hepatic metabolism. Previous studies have reported an increased plasma concentration of indoxyl sulfate in patients with renal impairment, implicating it as a cytochrome P450 (CYP) inhibiting factor. In this study, we aimed to assess steroid markers that represent hepatic CYP3A activity mediated by the renal function and to evaluate the association of indoxyl sulfate in patients with renal impairment.

Methods: Seventy-one subjects were enrolled in this study; based on estimated glomerular filtration rate (eGFR), they were classified as having mild, moderate, or severe renal impairment. The plasma concentration of indoxyl sulfate was quantified using LC-MS. Urinary and plasma markers (6β-OH-cortisol/cortisol, 6β-OH-cortisone/cortisone, and 4β-OH-cholesterol) for CYP3A activity were quantified using GC-MS. The correlation between variables was assessed using Pearson's correlation test.

Results: There was a significant negative correlation between eGFR and indoxyl sulfate levels. Among the steroid metabolic markers, 6β-OH-cortisone/cortisone showed a significant positive correlation with eGFR. There was a negative correlation between the plasma concentration of indoxyl sulfate and 4β-OH-cholesterol.

Conclusions: CYP3A activity may be inhibited via accumulation of plasma indoxyl sulfate resulting from renal impairment.