Influence of common variants in the pharmacokinetic genes (OATP-C, UGT1A1, and MRP2) on serum bilirubin levels in healthy subjects.
To assess the contribution of OATP-C to the hepatobiliary transport of bilirubin, a pharmacogenomic evaluation with regard to polymorphisms of three candidate genes, OATP-C, MRP2, and UGT1A1, was performed. Serum total and direct (conjugated) bilirubin levels were used as phenotypic indexes. Pharmacokinetic variables of pravastatin, a typical substrate for OATP-C, were obtained from our previous study. Among 23 volunteers, two variants (Val417Ile and Ser789Phe) were observed in the MRP2 gene. While there was no apparent effect of these two variants and the UGT1A1*28 on direct bilirubin levels, the OATP-C variants were associated with differences in unconjugated bilirubin levels. Subjects with the OATP-C*15 allele had higher bilirubin levels; unconjugated bilirubin levels in *1b/*1b (n = 3), *1b/*15 (n= 7), and *15/*15 (n = 1) subjects were 0.40 +/- 0.10, 0.77 +/- 0.35, and 0.70 (mg/dL), respectively. In addition, the correlation between unconjugated bilirubin levels and pharmacokinetic parameters of pravastatin revealed that the subjects with higher bilirubin levels had lower non-renal clearance values, and then higher serum concentrations of pravastatin. Large clinical studies are needed to confirm a role of OATP-C in the carrier-mediated uptake of bilirubin in the human liver.
Ieiri
Ichiro
I
Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Nishi-machi 36-1, Yonago, Tottori 6838504, Japan.
Suzuki
Hiroshi
H
Kimura
Miyuki
M
Takane
Hiroshi
H
Nishizato
Yohei
Y
Irie
Shin
S
Urae
Akinori
A
Kawabata
Kiyoshi
K
Higuchi
Shun
S
Otsubo
Kenji
K
Sugiyama
Yuichi
Y