CYP3A4*18B, CYP3A5*3, and MDR1C3435T gene studies with tacrolimus pharmacokinetics in healthy Chinese subjects

Aims: To investigate the effects of the CYP3A4*18B, CYP3A5*3, and MDR1C3435T gene polymorphisms on the pharmacokinetics of tacrolimus in healthy Chinese subjects. Methods: Thirty healthy Chinese subjects received single oral doses of 5 mg tacrolimus and were genotyped for CYP3A4*18B, CYP3A5*3, and MDR1C3435T using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The blood concentrations of tacrolimus were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS) up to 96 h after dosing. Results: The mean tacrolimus AUC0-96, AUC0-∞ and Cmax for the CYP3A4*1/*1 carriers were 282.81±202.13 ng·h·mL-1, 308.68±211.16 ng·h·mL-1 and 38.05±30.30 ng·mL-1, respectively, which were 3.96-fold, 3.70-fold and 3.88-fold greater than those of the CYP3A4*18B/*18B carriers (71.39±21.61 ng·h·mL-1, 83.38±29.00 ng·h·mL-1 and 9.80±2.60 ng·mL-1, respectively) (P= 0.001, 0.001 and 0.004, respectively). Similarly, the AUC0–96, AUC0-∞ and Cmax for the CYP3A5*3/*3 carriers were 238.27±178.82 ng·h·mL-1, 263.78±190.72 ng·h·mL-1 and 32.53±24.52 ng·mL-1, respectively, which were 2.52-, 2.48- and 2.27-fold greater than those of the CYP3A5*1 carriers (94.69±37.70 ng·h·mL-1, 106.28±41.46 ng·h·mL-1 and 14.30±5.77 ng·mL-1, respectively) (P=0.001, 0.001 and 0.004, respectively). Although there were no significant differences in pharmacokinetics among MDR1C3435T genotypes (P>0.05), the Tmax for MDR1 CC (1.25±0.27 h) homozygotes in CYP3A4 expressers (*18B/*18B or *1/*18B genotype) was much lower than that for the MDR1 T carriers (1.82±0.72 h) (P<0.05). In addition, sex, age, alanine aminotransferase (ALT) level, haematocrit (HCT) level, serum creatinine (SCr) level, gamma-glutamyl transferase (GGT) level, and CYP3A4*18B and CYP3A5*3 gene polymorphisms affected the pharmacokinetics of tacrolimus. Conclusions: CYP3A4*18B and CYP3A5*3 are important genetic factors influencing the pharmacokinetics of tacrolimus in the Chinese population.