Journal
PHARMACOLOGICAL REPORTS
Volume 63, Issue 3, Pages 815-825Publisher
POLISH ACAD SCIENCES INST PHARMACOLOGY
DOI: 10.1016/S1734-1140(11)70594-1
Keywords
ABCB1; bone marrow transplantation; cyclosporine A; CYP3A4*18B; CYP3A5*3; hematopoietic stem cell transplantation
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Funding
- National Natural Science Foundation of China [30973597]
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The aim of this study was to retrospectively evaluate the effect of polymorphisms in the CYP3A4,CYP3A5 and ABCB1 genes on the dose-adjusted concentration and dose requirement of cyclosporine A (CsA) in Chinese recipients during the early period after bone marrow or hematopoietic stem cell transplantation. Ninety-one bone marrow transplant recipients were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay or by direct sequencing for the C1236T, G2677T/A and C3435T polymorphisms in CYP3A4*18B, CYP3A5*3, and ABCB1, respectively. The concentration at zero before administration (C(0)) and concentration at 2 h after administration (C(2)) of whole blood CsA were measured by fluorescence polarization immunoassay. Dose-adjusted C(0) and C(2) were determined and compared among groups with different genotypes. Compared with CYP3A5*3/*3 individuals, CYP3A5*1/*1 subjects have a significantly lower dose-adjusted C(0) and C(2) at days 1-10 and a higher dose requirement for CsA at days 16-30 (p < 0.05). In addition, homozygotes for the ABCB1 3435T mutant have a significantly higher dose-adjusted C(0) and C2 and a lower dose requirement compared with wildtype (p < 0.05). Similar results were also derived for carriers of the T-G-C haplotype in CYP3A5 producers compared with non-carriers (p < 0.05 and p < 0.01, respectively). In summary, the ABCB1 3435T SNP, T-G-C haplotype in CYP3A5 producers, and CYP3A5*3 SNP are all associated with differences in CsA pharmacokinetics and dose requirements during the first month after bone marrow or hematopoietic stem cell transplantation. Genetic testing can therefore help to determine initial dosage and individualize immunosuppressive therapy.
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