The Influence of Cytochrome P450 3A Gene Polymorphisms on Tacrolimus Concentrations in Hematopoetic Stem Cell Transplantation Patients.

Objective: Tacrolimus is a commonly used immunosuppressive drug in hematopoetic stem cell transplantation (SCT). It is characterized by a relatively narrow therapeutic range and a large individual variation in concentrations. It is metabolized mainly by cytochrome P450 (CYP) 3A which has genetic polymorphisms influencing enzymatic activities; CYP3AP1*1 and *3 genotypes representexpressor and non-expressor, respectively. The objective of this study is to investigate whether the tacrolimusconcentration per dose and renal toxicity by tacrolimus is associated with CYP3AP1 gene polymorphisms.

Methods: 105 Japanese SCT patients (55 AML, 19 ALL, 11 CML, 6 MDS, 4 NHL, 1 HL, 2 ATL, 2 MM, 4 AA, 1 MF), receiving tacrolimus were studied. DNA was extracted from peripheral blood samples. CYP3AP1 genotype was analyzed by PCR-restriction fragment length polymorphism using specific primers and a restriction enzyme, AciI. Blood tacrolimus concentrations were measured twice a week by a commercially available EISA kit.

Results: The frequency of the CYP3AP1 *1/*1, *1/*3 and *3/*3 genotype was 8, 31, and 61% of 105 patients, respectively, and the genotype distribution was not different significantly from that of 121 Japanese healthy volunteers (3, 39, and 58%, respectively). The frequency of CYP3AP1 genotypes of white Americans is reported to be 2, 12 and 86%, respectively, indicating the ethnic difference of distribution. The dose-adjusted concentrations of tacrolimus 5 to 7 days following SCT were significantly higher in CYP3AP1 *3/*3 patients than in CYP3AP1 *1/*1 and *1/*3 patients (665.0±148.0 ng/ml per mg/kg vs. 409.0±116.2 ng/ml per mg/kg, P<0.001). The dose needed to achieve the target concentration (10 to 15 ng/ml) between 40 to 60 days following SCT, when the blood concentrations of tacrolimus tended to be stable in most patients, is significantly lower in CYP3AP1 *3/*3 patients than in CYP3AP1 *1/*1 and *1/*3 patients (0.008±0.005 mg/kg vs.0.018±0.005 mg/kg, P<0.001). Above grade two adverse events related to tacrolimus were observed only in CYP3AP1 *3/*3 patients (3 patients in grade 4 and 6 patient in grade2), suggesting the contribution of a higher concentration to renal toxicity by tacrolimus.

Conclusion: The tacrolimus concentration per dose in SCT patients is influenced by the CYP3AP1 gene polymorphism. This is the first report showing the relationship between CYP3AP1 gene polymorphism and the tacrolimus concentration in SCT patients to the best of our knowledge. Information of CYP3AP1 genotype may be helpful to determine the initial tacrolimus dose adequate for each patient.