CYP3A5 polymorphisms and their effects on tacrolimus exposure in an ethnically diverse South African renal transplant population
| Autor: | Robert Freercks, Doreen Zvipo Mhandire, K Manning, Collet Dandara, Zunaid Barday, J Ensor, W K Muller |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male medicine.medical_specialty Genotype medicine.medical_treatment Population Renal function Polymorphism Single Nucleotide Gastroenterology Tacrolimus Cohort Studies South Africa chemistry.chemical_compound Interquartile range Internal medicine Cytochrome P-450 CYP3A Humans Medicine education Retrospective Studies Creatinine education.field_of_study Dose-Response Relationship Drug business.industry Racial Groups Genetic Variation Immunosuppression General Medicine Middle Aged Kidney Transplantation Transplantation surgical procedures operative chemistry Female business Immunosuppressive Agents |
| Zdroj: | SAMJ: South African Medical Journal, Volume: 110, Issue: 2, Pages: 159-166, Published: FEB 2020 |
| Popis: | Background. Tacrolimus forms the cornerstone for immunosuppression in solid-organ transplantation. It has a narrow therapeutic window with wide inter- and intra-patient variability (IPV). Cytochrome P-450 3A5 (CYP3A5) is the main enzyme involved in tacrolimus metabolism, and rs776746A>G is the most frequently studied polymorphism in the CYP3A5 gene. The rs776746A>G (i.e. CYP3A5*3 ) single-nucleotide polymorphism in CYP3A5 alters tacrolimus predose trough concentration (C0) and may also affect IPV, which may lead to immune- and/or drug-mediated allograft injury. CYP3A5*3 may result in absent ( *3/*3 ) , partial ( *1/*3 ) or normal ( *1/*1 ) CYP3A5 expression. The effect of CYP3A5 *3 on tacrolimus exposure and variability has not been examined in South African (SA) transplant recipients. Objectives. To determine the frequencies and effect of CYP3A5 and adenosine triphosphate-binding cassette subfamily B member 1 ( ABCB1 ) polymorphisms on tacrolimus C0/dose ratios in different ethnic groups attending a tertiary renal transplant clinic in SA, and other factors that may explain inter- and IPV in tacrolimus C0. Methods. All consenting stable renal transplant recipients on tacrolimus at the Livingstone Hospital Renal Unit in Port Elizabeth, SA, were included. Tacrolimus concentrations were obtained using a microparticle enzyme immunoassay method (ARCHITECT analyser, Abbott Laboratories). Polymerase chain reaction/restriction fragment length polymorphism was used to genotype for CYP3A5*3 and *6 allelic variants. Results. There were 43 participants (35% black African, 44% mixed ancestry and 21% white), with a mean age of 44.5 years, median duration post-transplant of 47 months and median (interquartile range) creatinine and estimated glomerular filtration rate levels of 118 (92 - 140) µmol/L and 62 (49 - 76) mL/min at study inclusion. The mean tacrolimus C0 in the study was 6.7 ng/mL, with no difference across the different ethnic groups. However, the mean total daily dose of tacrolimus required was 9.1 mg (0.12 mg/kg), 7.2 mg (0.09 mg/kg) and 4.3 mg (0.06 mg/kg) in black, mixed-ancestry and white patients, respectively ( p =0.017). The frequencies for CYP3A5 expressors (i.e. CYP3A5*1/*1 + CYP3A5*1/*3 genotypes) were 72%, 100%, 76% and 12% for all patients combined and black, mixed-ancestry and white patients, respectively. The frequencies for CYP3A5 non-expressors (i.e. CYP3A5*3/*3 genotypes) were 0%, 24% and 88% among the black, mixed-ancestry and white patients, respectively. None of the patients carried the CYP3A5*6 allele. CYP3A5*1/*1 and CYP3A5*1/*3 genotype carriers required a two-fold increase in dose compared with the non-expressor genotype carriers, CYP3A5*3/*3 ( p |
| Databáze: | OpenAIRE |
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