Effect of the P450 oxidoreductase 28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers

• Published in: European journal of clinical pharmacology Vol. 69; no. 4; pp. 807 - 812
• Main Authors: Zhang, Jing-Jing, Zhang, Hua, Ding, Xiao-Liang, Ma, Sheng, Miao, Li-Yan
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.04.2013; Springer; Springer Nature B.V
• Subjects: Administration, Oral; Adult; Amplified Fragment Length Polymorphism Analysis; Asian Continental Ancestry Group - genetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; China; Chromatography, Liquid; Cytochrome P-450 CYP3A - genetics; Drug therapy; Gene Frequency; Genotype; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Kinetics; Male; Medical sciences; NADPH-Ferrihemoprotein Reductase - genetics; Pharmacogenetics; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Polymorphism; Polymorphism, Single Nucleotide; Tacrolimus - administration & dosage; Tacrolimus - blood; Tacrolimus - pharmacokinetics; Tandem Mass Spectrometry; Volunteers; Young Adult; Asia; China; Tacrolimus; Pharmacokinetics; POR28; CYP3A53; Human; Calcineurin inhibitor; Genetic variability; Healthy subject; Enzyme; Isozyme; Cytochrome P450; 28; Lactone; Genotype; Macrolide; CYP3A5; Immunomodulator; POR; 3; Chinese; Protein synthesis inhibitor; Immunosuppressive agent; Oxidoreductases; Polymorphism
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-012-1432-1

Purpose To assess the influence of the P450 oxidoreductase *28 SNP (POR*28) on tacrolimus pharmacokinetics in the Chinese population. Methods Seventy-one healthy Chinese volunteers enrolled in the study received an oral dose of 2 mg of tacrolimus after providing written informed consent. CYP3A5*3 was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and POR*28 was genotyped by PCR-direct sequencing. Tacrolimus whole blood concentrations were determined by ultra performance liquid chromatography-tandem mass spectrometry and the pharmacokinetics analyses was evaluated by nonparametric methods. Results The frequencies of CYP3A5*3 and POR*28 allele were 73.3 % and 29.6 %, respectively. No significant differences existed in tacrolimus pharmacokinetics between the POR*28 CC homozygotes ( n  = 32) and the POR*28 T allele ( n  = 39) in all subjects. The mean tacrolimus AUC 0–24 , AUC 0-∞ and C max for the POR*28 CC ( n  = 14) homozygotes in CYP3A5 expressers (CYP3A5*1/*1 or *1/*3 genotype) were 71.5 ± 38.9 h ng/mL, 94.3 ± 58.3 h ng/mL and 17.6 ± 9.8 ng/mL, which were much higher than the POR*28 CT heterozygotes ( n  = 17) of 46.7 ± 24.9 h ng/mL, 57.4 ± 33.9 h ng/mL and 11.2 ± 6.4 ng/mL ( P  < 0.05, respectively). We did not observe any significant differences in tacrolimus pharmacokinetics between the POR*28 CC homozygotes ( n  = 18) and POR*28 T carriers ( n  = 22) in CYP3A5 nonexpressers (CYP3A5*3/*3 carriers). Conclusions The POR*28 CT genotype presented a significantly lower level of tacrolimus exposure (AUC, C max ) compared with the POR*28 CC genotype in CYP3A5-expressing subjects. It suggested that the POR*28 genetic polymorphism might also be responsible for the marked interindividual variability of tacrolimus besides the CYP3A5*3 genetic polymorphism.