title: Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis.
abstract: OBJECTIVE
  Tacrolimus (TAC) is metabolized mainly by the CYP3A subfamily and extruded into the intestine by P-glycoprotein, which is encoded by the ABCB1 gene. Several studies have suggested that the CYP3A5*3 genotype influenced the pharmacokinetics (PK) of TAC. The CYP3A4*18B and CYP3A5*3 alleles are clinically important in Chinese subjects because of their relatively high frequency. The present study aimed at evaluating the effects of ABCB1 (C1236T-G2677T/A-C3435T), CYP3A4*18B and CYP3A5*3 genetic polymorphisms on TAC PK in healthy Chinese subjects.
  
  
  METHODS
  Data were obtained from a comparative bioavailability study of oral TAC formulations (n = 22). TAC whole blood concentrations were measured by LC-MS/MS. Genetic polymorphisms were determined using a direct sequencing method. Nonlinear mixed-effects modelling (NONMEM) was performed to assess the effect of genotypes and demographics on TAC PKs.
  
  
  CONCLUSIONS
  Both CYP3A4*18B and CYP3A5*3 polymorphisms affected the TAC PK, whereas ABCB1 genetic polymorphisms and other demographic characteristics did not. The combined genotypes of CYP3A4*18B and CYP3A5*3 had a greater impact than either genotype alone, and they were estimated to account for 28·4% of the inter-subject variability of apparent clearance (CL/F) by NONMEM. The CL/F in subjects with CYP3A4*1/*1-CYP3A5*3/*3 was 10·3 L/h and was 48·5% in those not carrying CYP3A4*1/*1-CYP3A5*3/*3.
  
  
  CONCLUSIONS
  This is the first study to extensively explore the influence of CYP3A4*18B, CYP3A5*3 and ABCB1 genetic polymorphisms on TAC PK in healthy Chinese subjects. The results demonstrated that subjects with a combined genotype of CYP3A4*1/*1-CYP3A5*3/*3 may require lower TAC doses to achieve target concentration levels and further investigation is needed in larger populations to confirm the clinical benefits.
authors.affiliation: Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: X-J
authors.initials: XJ
authors.lastname: Shi
authors.forename: F
authors.initials: F
authors.lastname: Geng
authors.forename: Z
authors.initials: Z
authors.lastname: Jiao
authors.forename: X-Y
authors.initials: XY
authors.lastname: Cui
authors.forename: X-Y
authors.initials: XY
authors.lastname: Qiu
authors.forename: M-K
authors.initials: MK
authors.lastname: Zhong
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D044466:Asian People / Q000235:genetics; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003710:Demography; D005260:Female; D005787:Gene Frequency; D005828:Genetics, Population / Q000379:methods* / Q000706:statistics & numerical data; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D007668:Kidney / Q000503:physiopathology; D016030:Kidney Transplantation; D008297:Male; D008954:Models, Biological; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011897:Random Allocation; D015203:Reproducibility of Results; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus