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Tacrolimus pharmacogenetics: Polymorphisms associated with expression of cytochrome P4503A5 and P-glycoprotein correlate with dose requirement

Macphee, IAM; Fredericks, S; Tai, T; Syrris, P; Carter, ND; Johnston, A; ... Holt, DW; + view all (2002) Tacrolimus pharmacogenetics: Polymorphisms associated with expression of cytochrome P4503A5 and P-glycoprotein correlate with dose requirement. TRANSPLANTATION , 74 (11) 1486 - 1489. 10.1097/01.TP.0000045761.71385.9F.

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Abstract

Background. There is marked heterogeneity in blood concentrations of tacrolimus following standard body-weight-based dosing. This is most apparent in black patients, who have a higher dose requirement when compared with other ethnic groups. Differences in intestinal P-glycoprotein and hepatic and intestinal cytochrome P4503A activity have been postulated as contributing to this problem.Methods. The dose-normalized blood concentrations of tacrolimus at 3 months after renal transplantation were related to CYP3AP1 and multiple drug resistance (MDR)-1 genotypes determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis.Results. We found that a single nucleotide polymorphism in the CYP3AP1 pseudogene (A/G(44)) that previously has been noted to be more common in African Americans and strongly associated with hepatic CYP3A5 activity correlated well with the tacrolimus dose requirement. A weaker association was found for a polymorphism in the MDR-1 gene, which influences intestinal P-glycoprotein expression.

Type:Article
Title:Tacrolimus pharmacogenetics: Polymorphisms associated with expression of cytochrome P4503A5 and P-glycoprotein correlate with dose requirement
DOI:10.1097/01.TP.0000045761.71385.9F
Keywords:TRANSPLANTATION, CYCLOSPORINE, FREQUENCY, GENE
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science

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