Impact of Concentrative Nucleoside Transporter 1 Gene Polymorphism on Oral Bioavailability of Mizoribine in Stable Kidney Transplant Recipients

Basic and Clinical Pharmacology and Toxicology - Tập 106 Số 4 - Trang 310-316 - 2010
Takafumi Naito1, Shunsuke Tokashiki2,1, Yasuaki Mino1, Atsushi Otsuka3, Seiichiro Ozono3, Yoshiyuki Kagawa4, Junichi Kawakami1
1Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
2Department of Clinical Pharmaceutics and Pharmacy Practice, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
3Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
4Department of Clinical Pharmaceutics & Pharmacy Practice, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

Tóm tắt

Abstract:  Mizoribine, an immunosuppressive anti‐metabolite, is largely excreted into urine in its unchanged form, and its pharmacokinetics has been considered to be dependent on the glomerular filtration rate. However, the pharmacokinetic disposition of mizoribine has not been fully clarified. The aim of this study was to evaluate the pharmacokinetic disposition of mizoribine based on polymorphism of concentrative nucleoside transporter (CNT) 1 gene in kidney transplant recipients. Thirty‐four Japanese stable recipients receiving an immunosuppressive regimen containing mizoribine for more than four months after transplantation were enrolled. Each recipient had been receiving a fixed dose of mizoribine for at least one month before enrolment. Oral bioavailability of mizoribine was obtained by dividing its amount in 24‐hr urine by the daily dose. The median and interquartile range of the dose‐normalized plasma concentration of mizoribine at 12 hr (C12) were 6.11 and 3.47–10.9 ng/ml per mg, respectively. The median bioavailability of mizoribine was 44.8%, and interindividual variability was also observed (interquartile range, 37.8–61.5%). The correlation coefficient between creatinine clearance and substitute renal clearance (CLMZ) estimated from the mizoribine C12 was 0.65. The CNT1 G565A allele frequency was 51.5%. The mizoribine bioavailability was significantly lower in 565GA and AA than that in GG (median, 42.0%, 41.4% and 62.4%, respectively). No significant differences were observed in the dose‐normalized C12 of mizoribine and substitute CLMZ between the G565A genotypes. The mizoribine bioavailability was affected by CNT1 G565A in kidney transplant recipients. CNT1 G565A would contribute to interindividual differences in plasma disposition of mizoribine.

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Thông tin xuất bản

Basic and Clinical Pharmacology and Toxicology

Tập 106 Số 4

310-316

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