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:	RM Therapeutics Pharmacology
Online Access:	https://ir.uitm.edu.my/id/eprint/15160/2/15160.pdf
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id	my-uitm-ir.15160
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spelling	my-uitm-ir.151602024-05-30T04:53:19Z The influence of genetic polymorphisms of CYP3A on the pharmacokinetic variation and clinical outcomes of tacrolimus in a cohort of patients / Mohd Rahimi Muda 2014 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 CYP3A418, CYP3A53 and CYP3A56 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 Five ml of blood were withdrawn from the 80 patients and the DNA was extracted, thus proceeded for genotyping of CYP3A418, CYP3A53 and CYP3A56 variants using two steps PCR technique.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 CYP3A418 (11.25%). As result of CYP3A53 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 CYP3A56 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 CYP3A418 and CYP3A53 genotypes respectively. Significant correlation between CYP3A53 genotypes with the doses has provided a reliable information in predicting the appropriate individual tacrolimus doses 2014 Thesis https://ir.uitm.edu.my/id/eprint/15160/ https://ir.uitm.edu.my/id/eprint/15160/2/15160.pdf text en public mphil masters Universiti Teknologi MARA Faculty of Pharmacy
institution	Universiti Teknologi MARA
collection	UiTM Institutional Repository
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 CYP3A418, CYP3A53 and CYP3A56 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 CYP3A418, CYP3A53 and CYP3A56 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 CYP3A418 (11.25%). As result of CYP3A53 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 CYP3A56 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 CYP3A418 and CYP3A53 genotypes respectively. Significant correlation between CYP3A53 genotypes with the doses has provided a reliable information in predicting the appropriate individual tacrolimus doses
format	Thesis
qualification_name	Master of Philosophy (M.Phil.)
qualification_level	Master's degree
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
granting_institution	Universiti Teknologi MARA
granting_department	Faculty of Pharmacy
publishDate	2014
url	https://ir.uitm.edu.my/id/eprint/15160/2/15160.pdf
_version_	1804889556337557504

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

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