Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis

Abstract

This is the first study to extensively explore the influence of CYP3A4*18B, CYP3A5*3 and ABCB1 genetic polymorphisms on TAC PK in healthy Chinese subjects. The results demonstrated that subjects with a combined genotype of CYP3A4*1/*1-CYP3A5*3/*3 may require lower TAC doses to achieve target concentration levels and further investigation is needed in larger populations to confirm the clinical benefits.

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

“…To date, an association between CYP3A4*1G and www.chinaphar.com Shu WY et al Acta Pharmacologica Sinica npg cyclosporine A pharmacokinetics has not been established in patients after transplantation [42,46,47] . Interestingly, two separate studies conducted by two hospitals located in different regions of China presented conflicting results, although both included Han Chinese [45,46] . One study [46] included subjects from Northeast China (Shenyang, Liaoning Province), a region in which ethnic minorities account for approximately 5% of the total population.…”

“…Notably, it was reported that CYP3A5*3 is associated with a higher cyclosporine A C 0 /dose in Han Chinese in North China [41] . Moreover, several studies of the CYP3A4*1G allele in intron 10 revealed that the CYP3A4*1G genotype had lower cyclosporine A clearance than CYP3A4*1/*1 in Han Chinese of East China [45] . To date, an association between CYP3A4*1G and www.chinaphar.com Shu WY et al Acta Pharmacologica Sinica npg cyclosporine A pharmacokinetics has not been established in patients after transplantation [42,46,47] .…”

“…One study [46] included subjects from Northeast China (Shenyang, Liaoning Province), a region in which ethnic minorities account for approximately 5% of the total population. The other study [45] was conducted in South China (Shanghai), where the majority of the population is Han Chinese. These conflicting results might be attributable to linkage disequilibrium (LD) between CYP3A4*1G and CYP3A5*3 in Asian populations [47][48][49] , including Han Chinese in South China [47] .…”

PharmGKB summary

“…Also known as rs28371759, the SNP is found in intron 10 of the CYP3A4 gene, is characterized by a G to A substitution, and is suggested to increase CYP3A4 activity [118]. Wild-type homozygotes for this allele had a reduced apparent clearance of tacrolimus compared with carriers of the mutant allele [138]. However, like rs2740574, this allele is also in LD with rs776746 [167].…”

Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China

“…Several studies have reported that the CYP3A5*3C/*3C genotype correlates with a higher CsA C 0 /dose in early renal transplant patients [6,7] , whereas other studies have demonstrated that the variant locus has no effect on the C 0 /dose [8,9] . Moreover, several studies on the high-frequency CYP3A4*1G allele in intron 10 revealed that the CYP3A4*1G/*1G genotype affects drug metabolism in healthy subjects, suggesting that CYP3A4*1G could affect CYP3A4 activity in vivo [10,11] . Other independent research groups did not observe a correlation between CYP3A4*1G and CsA pharmacokinetics in patients on the seventh day after renal transplantation or in early bone marrow transplant patients [7,12] .…”