J Korean Med Sci.  2018 Dec;33(53):e298. 10.3346/jkms.2018.33.e298.

Assessment of Hepatic Cytochrome P450 3A Activity Using Metabolic Markers in Patients with Renal Impairment

• Kim AH
• Yoon S
• Lee Y
• Lee J
• Bae E
• Lee H
• Kim DK
• Lee S
• Yu KS
• Jang IJ
• Cho JY

• KMID: 2429888
• DOI: http://doi.org/10.3346/jkms.2018.33.e298

Abstract

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 study has reported an increased plasma concentration of indoxyl sulfate and decreased plasma concentration of 4β-hydroxy (OH)-cholesterol in stable kidney transplant recipients, implicating indoxyl sulfate as a cytochrome P450 (CYP) inhibiting factor. In this study, we aimed to evaluate the impact of renal impairment severity-dependent accumulation of indoxyl sulfate on hepatic CYP3A activity using metabolic markers.
METHODS
Sixty-six 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 liquid chromatography-mass spectrometry (LC-MS). Urinary and plasma markers (6β-OH-cortisol/cortisol, 6β-OH-cortisone/cortisone, 4β-OH-cholesterol) for hepatic CYP3A activity were quantified using gas chromatography-mass spectrometry (GC-MS). The total plasma concentration of cholesterol was measured using the enzymatic colorimetric assay to calculate the 4β-OH-cholesterol/cholesterol ratio. The correlation between variables was assessed using Pearson's correlation test.
RESULTS
There was a significant negative correlation between MDRD eGFR and indoxyl sulfate levels. The levels of urinary 6β-OH-cortisol/cortisol and 6β-OH-cortisone/cortisone as well as plasma 4β-OH-cholesterol and 4β-OH-cholesterol/cholesterol were not correlated with MDRD eGFR and the plasma concentration of indoxyl sulfate.
CONCLUSION
Hepatic CYP3A activity may not be affected by renal impairment-induced accumulation of plasma indoxyl sulfate.

Keyword

Renal Impairment; Estimated Glomerular Filtration Rate; Indoxyl Sulfate; Cytochrome P450 3A; Metabolic Markers

MeSH Terms

Cholesterol
Cytochrome P-450 CYP3A*
Cytochrome P-450 Enzyme System*
Cytochromes*
Drug-Related Side Effects and Adverse Reactions
Gas Chromatography-Mass Spectrometry
Glomerular Filtration Rate
Humans
Indican
Kidney
Metabolism
Plasma
Spectrum Analysis
Transplant Recipients
Cholesterol
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System
Cytochromes
Indican