Phenotyping of CYP2C19 and CYP3A4 by Using Omeprazole as a Probe Drug and Genotyping of CYP2C19 for Common Allelic Variants in Ethiopians

Gebeyehu, Endalew (2008) Phenotyping of CYP2C19 and CYP3A4 by Using Omeprazole as a Probe Drug and Genotyping of CYP2C19 for Common Allelic Variants in Ethiopians. Masters thesis, Addis Ababa University.

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Abstract

Cytochrome P450 2C19 (CYP2C19) and cytochrome P450 3A4 (CYP3A4) are members of drug metabolizing CYP450 enzymes with documented genetic polymorphism that may cause marked interindividual and interethnic variation in the metabolism and disposition of their substrates. CYP450 enzymes activity can be assessed by making use of a variety of substrates. Although assessment of CYP2C19 activity using omeprazole as a probe is well documented, its use for CYP3A4 activity evaluation is not well recognized. The present study therefore attempted to assess CYP2C19 and CYP3A4 in Ethiopians and add to the existing body of evidence through phenotyping of CYP2C19 and CYP3A4 enzymes using omeprazole as a probe drug and to genotype CYP2C19 for the two common mutants alleles, CYP2C19*2 and CYP2C19*3. To this effect, one hundred fifty healthy Ethiopian volunteers were recruited and given 20 mg omeprazole orally. Plasma concentration of omeprazole, 5-hydroxy omeprazole and omeprazole sulfone was determined with HPLC. Logarithm transformed plasma concentration metabolic ratio (MR) of omeprazole /5-hydroxy omeprazole and omeprazole/omeprazole sulfone was used to evaluate activity of CYP2C19 and CYP3A4 enzymes, respectively. In addition, DNA was extracted from blood with E.Z.N.A.TM Blood DNA Kit and genotyping was performed with Taqman® allele discrimination for CYP2C19*2 and CYP2C19*3 alleles. The prevalence of extensive metabolizers (EMs) or poor metabolizers (PMs) was found to be 6% and 94%, respectively when CYP2C19 activity was assessed using a log MR cut off value of 0.8 between phenotypes. There was significant difference in the mean log MR value between PMs (1.121 ± 0.215) and EMs (0.120 ± 0.274) (P < 0.0001). Genotypic analysis revealed that two subjects (1.33%) were genotyped as PMs with CYP2C19*2/*2 genotype and 148 (98.67%) were genotyped as EMs, of which 76% were homozygous for CYP2C19*1/*1, 22.67% heterozygous for CYP2C19*1/*2 and CYP2C19*1/*3 genotype. No subjects with CYP2C19*2/*3 and CYP2C19*3/*3 genotype had been detected. Allelic frequency of CYP2C19*1, CYP2C19*2 and CYP2C19*3 were 262 (87%), 32 (11%) and 6(2%), respectively. The major allele that contributed for PMs was CYP2C19*2 and its frequency was comparable with that reported elsewhere. Correlation of phenotyping with genotyping revealed that whilst seven of genotype EMs were PMs on phenotyping, all genotype PMs were PMs on viii phenotyping. Assessment of CYP3A4 activity with log MR of omeprazole/omeprazole sulfone showed normal distribution with two outlier subjects of lower and higher activity. There were neither sex-dependent differences in the activity of both enzymes and nor any effect of CYP2C19 on CYP3A4 or vice versa during simultaneous assessment of these enzymes. These findings collectively indicate that consideration of dose adjustment is imperative in usage of particularly CYP2C19 substrate drugs and omeprazole could be used as a probe drug in simultaneous phenotyping of CYP2C19 and CYP3A4.

Item Type:	Thesis (Masters)
Uncontrolled Keywords:	Cytochrome P450, Genetic polymorphism, Extensive Metabolizer, Poor Metabolizer, Omeprazole, 5-hydroxy omeprazole, Omeprazole sulfone, Metabolic Ratio
Subjects:	Q Science > Q Science (General) R Medicine > RM Therapeutics. Pharmacology
Divisions:	Africana
Depositing User:	Vincent Mpoza
Date Deposited:	21 Jun 2018 07:10
Last Modified:	21 Jun 2018 07:10
URI:	http://thesisbank.jhia.ac.ke/id/eprint/5277

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