TY - JOUR T1 - Association of Plasma Concentration of 4<em>β</em>-Hydroxycholesterol with CYP3A5 Polymorphism and Plasma Concentration of Indoxyl Sulfate in Stable Kidney Transplant Recipients JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 105 LP - 110 DO - 10.1124/dmd.113.054171 VL - 42 IS - 1 AU - Yosuke Suzuki AU - Hiroki Itoh AU - Takashi Fujioka AU - Fuminori Sato AU - Kanako Kawasaki AU - Yukie Sato AU - Yuhki Sato AU - Keiko Ohno AU - Hiromitsu Mimata AU - Satoshi Kishino Y1 - 2014/01/01 UR - http://dmd.aspetjournals.org/content/42/1/105.abstract N2 - Several studies have shown that renal failure decreases CYP3A activity and that uremic toxins may play a role via transcriptional or translational modifications of cytochrome P450 (P450) enzymes and direct inhibition of P450-mediated metabolism. In this study, we evaluated the relationship between CYP3A activity (using plasma concentration of 4β-hydroxycholesterol as a biomarker) and clinical characteristics including plasma concentrations of indoxyl sulfate (3-INDS) and indole-3-acetic acid (3-IAA) in stable kidney transplant recipients. Forty-five Japanese kidney transplant recipients who underwent transplantation more than 90 days prior to the study were included. Morning blood samples were collected and plasma concentrations of 4β-hydroxycholesterol, 3-INDS, and 3-IAA were measured. Plasma concentrations of 4β-hydroxycholesterol were 57.1 ± 11.2, 42.1 ± 11.8, and 34.5 ± 7.3 ng/ml in recipients with CYP3A5*1/*1 (n = 5), *1/*3 (n = 15), and *3/*3 (n = 25) genotypes, respectively, with significant differences between three genotypes. A significant correlation was observed between plasma concentrations of 4β-hydroxycholesterol and 3-INDS but not 3-IAA. Multiple regression analysis identified the number of CYP3A5*3 alleles in genotype, plasma concentration of 3-INDS, and body weight as independent variables associated with plasma concentration of 4β-hydroxycholesterol. In conclusion, these results suggest that CYP3A5 polymorphism and plasma concentration of 3-INDS may account for the interindividual variability of CYP3A activity, and that plasma concentration of 3-INDS may partially explain the gap in CYP3A activity that cannot be explained by genetic contribution in patients with renal failure. ER -