Effect of CYP3A53 Polymorphism on Pharmacokinetic Drug Interaction between Tacrolimus and Amlodipine

• Published in: DRUG METABOLISM AND PHARMACOKINETICS Vol. 28; no. 5; pp. 398 - 405
• Main Authors: Zuo, Xiao-cong, Zhou, Ya-nan, Zhang, Bi-kui, Yang, Guo-ping, Cheng, Ze-neng, Yuan, Hong, Ouyang, Dong-sheng, Liu, Shi-kun, Barrett, Jeffrey S., Li, Pei-jiong, Liu, Zhi, Tan, Hong-yi, Guo, Ren, Zhou, Ling-yun, Xie, Yue-liang, Li, Zuo-jun, Li, Jing, Wang, Chun-jiang, Wang, Jiang-lin
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 2013; Japanese Society for the Study of Xenobiotics
• Subjects: amlodipine; Amlodipine - pharmacokinetics; CYP3A53 polymorphism; Cytochrome P-450 CYP3A - genetics; Drug Interactions; drug-drug interaction; Humans; Immunosuppressive Agents - pharmacokinetics; Male; pharmacokinetics; Polymorphism, Single Nucleotide; tacrolimus; Tacrolimus - administration & dosage; Tacrolimus - pharmacokinetics; Young Adult; pharmacokinetics; CYP3A53 polymorphism; drug-drug interaction; tacrolimus; amlodipine
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.2133/dmpk.DMPK-12-RG-148

The objective of this study was to evaluate the effect of the CYP3A5*3 allele on the pharmacokinetics of tacrolimus and amlodipine, and drug-drug interactions between them in healthy subjects. Pharmacokinetic drug interactions between tacrolimus and amlodipine were evaluated in a randomized, 3-period, 6-sequence crossover study in healthy Chinese volunteers according to CYP3A5 genotype. A single-dose and multiple-dose study were designed. A 96-h pharmacokinetic study followed either tacrolimus or amlodipine dose, and the washout periods between the study phases were 14 days. In the single-dose study, apparent oral clearance (CL/F) of tacrolimus (5 mg) in CYP3A5 expressers was 3.8-fold (p = 0.008) higher than that in CYP3A5 non-expressers. Amlodipine decreased mean tacrolimus CL/F in CYP3A5 expressers by 2.2-fold (p = 0.005), while it had no effect on that in CYP3A5 non-expressers. The CL/F of amlodipine in CYP3A5 non-expressers was 2.0-fold (p = 0.001) higher than that in CYP3A5 expressers. Tacrolimus increased mean amlodipine CL/F in CYP3A5 expressers by 1.4-fold (p = 0.016) while it had no effect on that in CYP3A5 non-expressers. Tacrolimus slightly reduced the AUC0−∞ of amlodipine in both CYP3A5 expressers and non-expressers. Dose adjustment of tacrolimus should be considered according to CYP3A5*3 genetic polymorphism when tacrolimus is coadministered with amlodipine.