title: Effect of CYP3A5*3 polymorphism on pharmacokinetic drug interaction between tacrolimus and amlodipine.
abstract: 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.
authors: Clinical Pharmacy and Pharmacology Research Institute, The Third Xiangya Hospital, Central South University.
authors: Xiao-cong
authors: XC
authors: Zuo
authors: Ya-nan
authors: YN
authors: Zhou
authors: Bi-kui
authors: BK
authors: Zhang
authors: Guo-ping
authors: GP
authors: Yang
authors: Ze-neng
authors: ZN
authors: Cheng
authors: Hong
authors: H
authors: Yuan
authors: Dong-sheng
authors: DS
authors: Ouyang
authors: Shi-kun
authors: SK
authors: Liu
authors: Jeffrey S
authors: JS
authors: Barrett
authors: Pei-jiong
authors: PJ
authors: Li
authors: Zhi
authors: Z
authors: Liu
authors: Hong-yi
authors: HY
authors: Tan
authors: Ren
authors: R
authors: Guo
authors: Ling-yun
authors: LY
authors: Zhou
authors: Yue-liang
authors: YL
authors: Xie
authors: Zuo-jun
authors: ZJ
authors: Li
authors: Jing
authors: J
authors: Li
authors: Chun-jiang
authors: CJ
authors: Wang
authors: Jiang-lin
authors: JL
authors: Wang
mesh_terms: D017311:Amlodipine / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D017311:Amlodipine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus