Influence of Genetic Polymorphisms on Tacrolimus Pharmacokinetics in Whole Blood, Plasma, and Peripheral Blood Mononuclear Cells in Chinese Kidney Allograft Recipients

BACKGROUND: Significant variations in tacrolimus (TAC) pharmacokinetics (PK) occur across whole blood, plasma, and peripheral blood mononuclear cells (PBMCs). In the present study, TAC plasma levels were estimated based on TAC whole blood levels, and the influence of genetic polymorphisms on the PKs of TAC were compared between whole blood, plasma, and PBMCs. METHODS: Whole blood, plasma, and PBMC samples of 36 kidney allograft recipients were collected at 0-12 hours after the morning dose after 1 month of therapy. TAC levels in whole blood (Cwb), plasma (Cp), and PBMCs were determined using liquid chromatography-tandem mass spectrometry. TAC Cp was estimated based on Cwb and hematocrit. PK parameters of TAC in whole blood, plasma, and PBMC were estimated. The influence of CYP3A5 and ABCB1 genotypes on TAC exposure was evaluated. RESULTS: TAC whole blood trough concentration (C0), maximum concentration (Cmax), and area under the concentration-time curve (AUC0-12) were 8.60 ± 5.59 ng/mL, 20.1 ± 7.69 ng/mL, and 144 ± 69.4 ng⋅h/mL, respectively; 0.21 ± 0.12 ng/mL, 0.51 ± 0.35 ng/mL, and 3.02 ± 1.68 ng⋅h/mL, respectively, in plasma; and 0.026 ± 0.017 ng/106 PBMCs, 0.078 ± 0.047 ng/106 PBMCs, 0.49 ± 0.30 ng⋅h/106 PBMCs, respectively. A moderate correlation was observed between C0, Cmax, and AUC0-12 in plasma and PBMCs (P < 0.05). Recipients with CYP3A5*3/*3 genotype exhibited a higher AUC0-12 in PBMC than those with the *1/*1 or *1/*3 genotypes (P < 0.05). Recipients with ABCB1 3435 TT genotype showed higher C0, Cmax, and AUC0-12 values in PBMC than those with the 3435CC or CT genotypes (P < 0.01). CONCLUSIONS: Plasma TAC concentrations in Chinese kidney allograft recipients can be estimated using whole blood TAC and hematocrit levels. Genetic polymorphisms of CYP3A5*3 and ABCB1 (3435C > T) significantly influenced TAC exposure in both plasma and PBMC.