ABCB1 genetic variant and its associated tacrolimus pharmacokinetics affect renal function in patients with rheumatoid arthritis

作者：Naito Takafumi^*; Mino Yasuaki; Aoki Yuki; Hirano Kumi; Shimoyama Kumiko; Ogawa Noriyoshi; Kagawa Yoshiyuki; Kawakami Junichi

来源：Clinica Chimica Acta, 2015, 445: 79-84.

DOI：10.1016/j.cca.2015.03.021

• Tacrolimus
• Rheumatoid arthritis
• ABCB1
• Genetic variant
• CYP3A5
• Renal function

Background: This study aimed to evaluate the blood exposure of and clinical responses to tacrolimus based on genetic variants of CYP3A5 and ABCB1 in patients with rheumatoid arthritis.
Methods: Seventy rheumatoid arthritis patients treated with oral tacrolimus once daily were enrolled. Blood concentrations of tacrolimus and its major metabolite 13-O-demethylate at 12 h after dosing were determined. The relationships between the tacrolimus pharmacokinetics and efficacy, renal function, and CYP3A5 and ABCB1 genotypes were evaluated.
Results: Dose-normalized blood concentration of tacrolimus was significantly higher in the CYP3A5*33 group than in the *1 allele carrier group. A lower metabolic ratio of 13-O-demethylate to tacrolimus was observed in the CYP3A5*33 group. The ABCB1 3435TT group had higher dose-normalized blood concentrations of tacrolimus and 13-O-demethylate. The blood tacrolimus concentration was inversely correlated with the estimated glomerular filtration rate (eGFR). ABCB1 C3435T but not CYP3A5 genotype had decreased eGFR. Patients lacking the CYP3A5*3 allele had a higher incidence of tacrolimus withdrawal.
Conclusion: CYP3A5*3 increased the blood exposure of tacrolimus through its metabolic reduction. ABCB1 C3435T led to a higher blood exposure of tacrolimus and its major metabolite. The ABCB1 genetic variant and its associated tacrolimus pharmacoldnetics affected renal function in rheumatoid arthritis patients.

• 出版日期2015-5-20