Tacrolimus dose requirement in relation to donor and recipient ABCB1 and CYP3A5 gene polymorphisms in Chinese liver transplant patients.
The aim of this study was to investigate whether the heterogeneity in tacrolimus dose requirement is associated with ABCB1 and CYP3A5 gene polymorphisms in Chinese liver transplant patients during the first month after transplantation. ABCB1 and CYP3A5 genotyping was performed using the polymerase chain reaction restriction sites polymorphism-based procedure in Chinese liver transplant recipients (n = 50) and their corresponding donors (n = 50). Tacrolimus whole-blood trough concentrations were measured by immunoassays on the IMx analyzers (Abbott Diagnostics Laboratories, Abbott-Park, IL). Doses required to achieve target blood concentrations and dose-adjusted trough concentrations (concentration/dose [C/D] ratios) were compared among patients according to allelic status of ABCB1 and CYP3A5. The ABCB1 3435CC was observed in 23 subjects (23%), whereas 64 (64%) carried 3435CT and 13 (13%) carried 3435TT. The CYP3A5*1/*1 was observed in 13 subjects (13%), 50 (50%) carried *1/*3, and 37 (37%) carried*3/*3. The tacrolimus C/D ratios were obviously lower in recipients carrying ABCB1 3435CC genotype. For CYP3A5, recipients who received organs from CYP3A5*3/*3 donors had higher C/D ratios. But the donors' ABCB1 and recipients' CYP3A5 genotype did not affect the recipients' pharmacokinetics. Analysis of the combination of recipients' ABCB1 and donors' CYP3A5 genotypes revealed that the tacrolimus C/D ratios were significantly lower in the ABCB1 3435CC-carrying recipients, regardless of donors' CYP3A5 genotype. In conclusion, our finding suggests that the recipients' ABCB1 and donors' CYP3A5 genotype affect the tacrolimus dose requirements. ABCB1 C3435T polymorphism is a major determinant of tacrolimus trough concentration in Chinese liver transplant recipients, and recipients with 3435CC genotype will require higher dose of tacrolimus.
Wei-lin
Wang
W
Department of Hepatobiliary Pancreatic Surgery, Key Lab of Combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital of Medical College, Zhejiang University, Hang Zhou, People's Republic of China.
Jing
Jin
J
Shu-sen
Zheng
Z
Li-hua
Wu
W
Ting-bo
Liang
L
Song-feng
Yu
Y
Sheng
Yan
Y
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage*; D014019:Tissue Donors
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027361:Organic Anion Transporters; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus