caa a22 4500 475818954 CHVBK 20180406123817.0 cr unu---uuuuu 170329e20000801xx s 000 0 eng 10.1007/s002280000166 doi (NATIONALLICENCE)springer-10.1007/s002280000166 Frequency of cytochrome P 450 3A4 variant genotype in transplant population and lack of association with cyclosporin clearance [Elektronische Daten] [L. P. Rivory, H. Qin, S. J. Clarke, J. Eris, G. Duggin, E. Ray, R. J. Trent, J. F. Bishop] Objective: Cytochrome P 450 3A4 (CYP3A4) plays a vital role in the oxidative metabolism of many xenobiotics. Some recent reports have provided circumstantial evidence in support of an association between a genetic polymorphism (A→G) in the 5′-flanking region (−290) of CYP3A4 and altered enzyme activity. We sought to determine whether genotyping patients for CYP3A4-G could assist with the dose optimisation of drugs metabolised by this system. Methods: Normal subjects and renal-transplant patients receiving cyclosporin for immune modulation were genotyped for the CYP3A4-G variant. A surrogate for cyclosporin clearance was estimated from the ratio of the cyclosporin dose, normalised for body weight and the corresponding trough concentration. The association between genotype and clearance was examined in patients who received twice-daily doses of cyclosporin and who were not on concurrent medication known to modify CYP3A4 function. Results: The allelic frequencies of the CYP3A4-G variant were estimated to be 2.6% and 3% in transplant patients and normal subjects, respectively. The median cyclosporin pseudo-clearance of transplant patients with wild-type CYP3A4 was 0.90 l/h/kg (range: 0.35-3.8 l/h/kg; n=86), whereas the corresponding value for the five patients heterozygotic for the CYP3A4-G variant was 0.71 l/h/kg (range 0.35-0.91 l/h/kg). The distribution of the pseudo-clearance according to genotype was not found to be significant according to a Fisher's exact test (P=0.15). Conclusion: Genotyping for the CYP3A4-G polymorphism is unlikely to assist cyclosporin dose selection in transplant patients. Springer-Verlag Berlin Heidelberg, 2000 Key words Cytochrome P450 3A4 nationallicence Cyclosporin nationallicence Transplant nationallicence Rivory L. P. Department of Pharmacology, University of Sydney, Sydney NSW 2006, Australia, AU aut Qin H. Molecular Genetics, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia, AU aut Clarke S. J. Medical Oncology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia e-mail: lrivory@canc.rpa.cs.nsw.gov.au Tel.: +61-2-95157376; Fax +61-2-95191546, AU aut Eris J. Renal Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia, AU aut Duggin G. Renal Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia, AU aut Ray E. Renal Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia, AU aut Trent R. J. Molecular Genetics, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia, AU aut Bishop J. F. Medical Oncology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia e-mail: lrivory@canc.rpa.cs.nsw.gov.au Tel.: +61-2-95157376; Fax +61-2-95191546, AU aut https://doi.org/10.1007/s002280000166 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280000166 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Rivory L. P. Department of Pharmacology, University of Sydney, Sydney NSW 2006, Australia, AU aut NATIONALLICENCE 700 1- Qin H. Molecular Genetics, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia, AU aut NATIONALLICENCE 700 1- Clarke S. J. Medical Oncology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia e-mail: lrivory@canc.rpa.cs.nsw.gov.au Tel.: +61-2-95157376; Fax +61-2-95191546, AU aut NATIONALLICENCE 700 1- Eris J. Renal Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia, AU aut NATIONALLICENCE 700 1- Duggin G. Renal Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia, AU aut NATIONALLICENCE 700 1- Ray E. Renal Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia, AU aut NATIONALLICENCE 700 1- Trent R. J. Molecular Genetics, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia, AU aut NATIONALLICENCE 700 1- Bishop J. F. Medical Oncology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia e-mail: lrivory@canc.rpa.cs.nsw.gov.au Tel.: +61-2-95157376; Fax +61-2-95191546, AU aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer