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- Title
Influence of the CYP3A5 and MDR1 genetic polymorphisms on the pharmacokinetics of tacrolimus in healthy Korean subjects.
- Authors
Choi, Ji H..; Lee, Yoon J.; Jang, Seong B.; Lee, Jong-Eun; Kim, Kyung H.; Park, Kyungsoo
- Abstract
What is already known about this subject • It was found that the genetic polymorphisms of CYP3A5, CYP3A4 and MDR1 could affect the pharmacokinetics of tacrolimus. • This study was conducted to find such a possibility in the Korean population. What this study adds • CYP3A5 polymorphisms are likely to be associated with altered pharmacokinetics of tacrolimus in Koreans. • MDR1 polymorphisms have no important role in the pharmacokinetics of tacrolimus. Aims To determine the frequencies of the genotypes of CYP3A5 and MDR1 and to examine the influence of the polymorphisms of these genes on tacrolimus pharmacokinetics in the Korean population. Methods Twenty-nine healthy Koreans who participated in the previous tacrolimus pharmacokinetic study were genotyped for CYP3A4* 1B, CYP3A5* 3, MDR1 c.1236C→T, MDR1 c.2677G→A/T and MDR1 c.3435C→T. The relationship between the genotypes so obtained and tacrolimus pharmacokinetics observed in the previous study was examined. Results No subject in this study had the CYP3A4* 1B variant. The observed frequencies of CYP3A5* 1/* 1, * 1/* 3, and * 3/* 3 were 0.069 [confidence interval (CI) −0.023, 0.161], 0.483 (CI 0.301, 0.665) and 0.448 (CI 0.267, 0.629), respectively. AUC0–∞ for the CYP3A5* 1/* 1 or * 1/* 3 genotype was 131.5 ± 44.8 ng h ml−1 (CI 109.6, 153.5), which was much lower compared with the CYP3A5* 3/* 3 genotype of 323.8 ± 129.3 ng h ml−1 (CI 253.5, 394.1) ( P = 2.063E−07). Similarly, Cmax for the CYP3A5* 1/* 1 or * 1/* 3 genotype was 11.8 ± 3.4 ng ml−1 (CI 10.1, 13.5), which was also much lower compared with the CYP3A5* 3/* 3 genotype of 24.4 ± 12.3 ng ml−1 (CI 17.8, 31.1) ( P = 0.0001). However, there was no significant difference in tacrolimus pharmacokinetics among the MDR1 diplotypes of CGC-CGC, CGC-TTT, CGC-TGC, TTT-TGC or TTT-TTT ( P = 0.2486). Conclusions This study shows that the CYP3A5* 3 genetic polymorphisms may be associated with the individual difference in tacrolimus pharmacokinetics. An individualized dosage regimen design incorporating such genetic information would help increase clinical efficacy of the drug while reducing adverse drug reactions.
- Subjects
PHARMACEUTICAL research; GENETIC polymorphisms; TACROLIMUS; PHARMACOKINETICS; KOREANS; DRUG side effects; DRUG efficacy
- Publication
British Journal of Clinical Pharmacology, 2007, Vol 64, Issue 2, p185
- ISSN
0306-5251
- Publication type
Article
- DOI
10.1111/j.1365-2125.2007.02874.x