Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis.
Summary What is known and 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*...
| Publicado en: | Journal of Clinical Pharmacy & Therapeutics Vol. 36; no. 5; pp. 614 - 625 |
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| Autores principales: | , , , , , |
| Formato: | equations & formulas research tables/charts Journal Article |
| Publicado: |
Wiley-Blackwell
Oct2011
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=104685569&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 104685569 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 02694727 EV4 jtl: Journal of Clinical Pharmacy & Therapeutics issn: 02694727 maglogo: Y pubinfo: dt: Oct2011 vid: 36 iid: 5 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 104685569 65430247 10.1111/j.1365-2710.2010.01206.x NLM21916909 104685569 ppf: 614 ppct: 11 formats: fmt: @attributes: type: P tig: atl: Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis. aug: au: Shi, X.-J. Geng, F. Jiao, Z. Cui, X.-Y. Qiu, X.-Y. Zhong, M.-K. affil: Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, Shanghai, China sug: subj: Genotype Antibiotics, Macrolide Pharmacokinetics Chinese Persons Antibiotics, Macrolide Metabolism Polymorphism, Genetic Drug Effects Immunosuppressive Agents Pharmacokinetics Biological Availability Antibiotics, Macrolide Blood Mass Spectrometry Chromatography, Liquid Sequence Analysis Antibiotics, Macrolide Administration and Dosage Administration, Oral Data Analysis Software Analysis of Covariance Chi Square Test Models, Statistical Human Male Female Adult Descriptive Statistics Univariate Statistics Funding Source Adult: 19-44 years Male Female ab: Summary What is known and 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. Results and Discussion: 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. What is new and Conclusion: 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. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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