CYP3A4∗18B and CYP3A5∗3 polymorphisms contribute to pharmacokinetic variability of cyclosporine among healthy Chinese subjects.

AIM

Cyclosporine is an immunosuppressant drug used to prevent allograft rejection. It is metabolized by CYP3A4 and CYP3A5, has a narrow therapeutic index, and variable pharmacokinetics. Here, we investigated whether CYP3A5∗3 and CYP3A4∗18B polymorphisms contribute to inter-individual pharmacokinetic variability in healthy subjects.

PATIENTS AND METHODS

Fifty-six healthy Chinese subjects were enrolled in the study after signing a written consent. The subjects received 5mgkg(-1) of cyclosporine orally and were genotyped for CYP3A5∗3 and CYP3A4∗18B using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Blood concentrations of cyclosporine were measured by high-performance liquid chromatography for up to 30h post-dose.

RESULTS

The mean cyclosporine AUC0→30 and AUC0→∞ in the male group was significantly higher than that in the female group (P=0.037 and 0.035); the CL/F in the male group was significantly lower than that in the female group (P=0.033). The Cmax of cyclosporine in CYP3A4∗1/∗1 was significantly greater than that in CYP3A4∗1/∗18B in the male group (P=0.023), but not the female group. In addition, the Cmax in CYP3A5∗1/∗3 was significantly lower than that in CYP3A5∗3/∗3 in the male group (P=0.01).

CONCLUSIONS

The results indicate that gender and polymorphism in CYP3A4∗18B and CYP3A5∗3 significantly affect cyclosporine pharmacokinetics in healthy subjects.