The influence of genetic polymorphisms of CYP3A on the pharmacokinetic variation and clinical outcomes of tacrolimus in a cohort of patients / Mohd Rahimi Muda

The complexity of determining the variability in tacrolimus pharmacokinetics parameter among organ transplant patients and its narrow therapeutic window characteristics necessitates proper drug monitoring in order to ensure the level is maintained within therapeutic range. Many studies have reported...

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Main Author: Muda, Mohd Rahimi
Format: Thesis
Language:English
Published: 2014
Subjects:
Online Access:http://ir.uitm.edu.my/id/eprint/15160/
http://ir.uitm.edu.my/id/eprint/15160/1/TM_MOHD%20RAHIMI%20MUDA%20PH%2014_5.pdf
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spelling uitm-151602016-11-11T05:29:54Z http://ir.uitm.edu.my/id/eprint/15160/ The influence of genetic polymorphisms of CYP3A on the pharmacokinetic variation and clinical outcomes of tacrolimus in a cohort of patients / Mohd Rahimi Muda Muda, Mohd Rahimi RM Therapeutics. Pharmacology The complexity of determining the variability in tacrolimus pharmacokinetics parameter among organ transplant patients and its narrow therapeutic window characteristics necessitates proper drug monitoring in order to ensure the level is maintained within therapeutic range. Many studies have reported that variability of tacrolimus pharmacokinetics was due to differential expression of drug metabolizing enzymes CYP3A4 and CYP3A5 encoded by CYP3A4 and CYP3A5 genes respectively. The aim of the study was to develop a genotyping method in detecting CYP3A4*18, CYP3A5*3 and CYP3A5*6 mutations as well as investigating any correlation of genotyping findings with the clinical and tacrolimus related pharmacokinetics data and to quantify enzyme expression through the relationship of CYP3A4 and CYP3A5 mRNA copy number with the patients’ genotypes. Five ml of blood were withdrawn from the 80 patients and the DNA was extracted, thus proceeded for genotyping of CYP3A4*18, CYP3A5*3 and CYP3A5*6 variants using two steps PCR technique. Absolute quantification was employed where the serial dilution of plasmid from cloned bacteria to generate a standard curve was done prior to real time PCR method. Nine of 80 patients were found to be heterozygous of CYP3A4*18 (11.25%). As result of CYP3A5*3 polymorphism, eight patients were found as homozygous wild type (10%), 31 patients were heterozygous (38.75%) and 41 patients were homozygous mutant (51.25%). No CYP3A5*6 mutation was observed in this study. Homozygous mutant was significantly associated with lowest requirement of tacrolimus dose and highest adjusted level per dose (P<0.01). There was no significant correlation between CYP3A4 and CYP3A5 mRNA copy number with the CYP3A4*18 and CYP3A5*3 genotypes respectively. Significant correlation between CYP3A5*3 genotypes with the doses has provided a reliable information in predicting the appropriate individual tacrolimus doses 2014 Thesis NonPeerReviewed text en http://ir.uitm.edu.my/id/eprint/15160/1/TM_MOHD%20RAHIMI%20MUDA%20PH%2014_5.pdf Muda, Mohd Rahimi (2014) The influence of genetic polymorphisms of CYP3A on the pharmacokinetic variation and clinical outcomes of tacrolimus in a cohort of patients / Mohd Rahimi Muda. Masters thesis, Universiti Teknologi MARA.
repository_type Digital Repository
institution_category Local University
institution Universiti Teknologi MARA
building UiTM Institutional Repository
collection Online Access
language English
topic RM Therapeutics. Pharmacology
spellingShingle RM Therapeutics. Pharmacology
Muda, Mohd Rahimi
The influence of genetic polymorphisms of CYP3A on the pharmacokinetic variation and clinical outcomes of tacrolimus in a cohort of patients / Mohd Rahimi Muda
description The complexity of determining the variability in tacrolimus pharmacokinetics parameter among organ transplant patients and its narrow therapeutic window characteristics necessitates proper drug monitoring in order to ensure the level is maintained within therapeutic range. Many studies have reported that variability of tacrolimus pharmacokinetics was due to differential expression of drug metabolizing enzymes CYP3A4 and CYP3A5 encoded by CYP3A4 and CYP3A5 genes respectively. The aim of the study was to develop a genotyping method in detecting CYP3A4*18, CYP3A5*3 and CYP3A5*6 mutations as well as investigating any correlation of genotyping findings with the clinical and tacrolimus related pharmacokinetics data and to quantify enzyme expression through the relationship of CYP3A4 and CYP3A5 mRNA copy number with the patients’ genotypes. Five ml of blood were withdrawn from the 80 patients and the DNA was extracted, thus proceeded for genotyping of CYP3A4*18, CYP3A5*3 and CYP3A5*6 variants using two steps PCR technique. Absolute quantification was employed where the serial dilution of plasmid from cloned bacteria to generate a standard curve was done prior to real time PCR method. Nine of 80 patients were found to be heterozygous of CYP3A4*18 (11.25%). As result of CYP3A5*3 polymorphism, eight patients were found as homozygous wild type (10%), 31 patients were heterozygous (38.75%) and 41 patients were homozygous mutant (51.25%). No CYP3A5*6 mutation was observed in this study. Homozygous mutant was significantly associated with lowest requirement of tacrolimus dose and highest adjusted level per dose (P<0.01). There was no significant correlation between CYP3A4 and CYP3A5 mRNA copy number with the CYP3A4*18 and CYP3A5*3 genotypes respectively. Significant correlation between CYP3A5*3 genotypes with the doses has provided a reliable information in predicting the appropriate individual tacrolimus doses
format Thesis
author Muda, Mohd Rahimi
author_facet Muda, Mohd Rahimi
author_sort Muda, Mohd Rahimi
title The influence of genetic polymorphisms of CYP3A on the pharmacokinetic variation and clinical outcomes of tacrolimus in a cohort of patients / Mohd Rahimi Muda
title_short The influence of genetic polymorphisms of CYP3A on the pharmacokinetic variation and clinical outcomes of tacrolimus in a cohort of patients / Mohd Rahimi Muda
title_full The influence of genetic polymorphisms of CYP3A on the pharmacokinetic variation and clinical outcomes of tacrolimus in a cohort of patients / Mohd Rahimi Muda
title_fullStr The influence of genetic polymorphisms of CYP3A on the pharmacokinetic variation and clinical outcomes of tacrolimus in a cohort of patients / Mohd Rahimi Muda
title_full_unstemmed The influence of genetic polymorphisms of CYP3A on the pharmacokinetic variation and clinical outcomes of tacrolimus in a cohort of patients / Mohd Rahimi Muda
title_sort influence of genetic polymorphisms of cyp3a on the pharmacokinetic variation and clinical outcomes of tacrolimus in a cohort of patients / mohd rahimi muda
publishDate 2014
url http://ir.uitm.edu.my/id/eprint/15160/
http://ir.uitm.edu.my/id/eprint/15160/1/TM_MOHD%20RAHIMI%20MUDA%20PH%2014_5.pdf
first_indexed 2023-09-18T22:53:14Z
last_indexed 2023-09-18T22:53:14Z
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