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• W2158824094 abstract "Individuals vary widely in their response to drug treatment. After receiving doses of a drug that are recommended based on a population average, some patients could have an insufficient response, whereas others may experience adverse effects. Of the many factors causing variability in drug response across individuals, genetic polymorphism of drug-metabolizing enzymes is deemed to be one of the valuable independent predictors of this variability. CYP2C19 is an important polymorphically expressed enzyme known to catalyze the metabolism of several widely prescribed drugs, including omeprazole, warfarin (R-enantiomer), and citalopram/escitalopram. The impact of CYP2C19 polymorphisms on the pharmacokinetics (PK) of its substrates and corresponding clinical relevance are of great interest.The aim of this thesis is to investigate the influence of CYP2C19 polymorphisms on PK and pharmacodynamics (PD) of clinically important CYP2C19 substrates (e.g., omeprazole, citalopram, and warfarin), and to advance the understanding of their inter-individual variability in drug therapy. We quantified the effect of functional CYP2C19 allele variants, including the gain-of- function allele (CYP2C19*17), on drug exposure and response in order to facilitate personalized dose selection.In Paper I, we studied the disposition of omeprazole and its effect on plasma gastrin levels following single and multiple doses in the three phenotype groups (extensive metabolisers [EMs], intermediate metabolisers [IMs], and poor metabolisers [PMs]) of S- mephenytoin hydroxylation. When 20 mg of omeprazole was given orally for 8 days on a once-daily (QD) regimen, the relative AUC ratios in EMs, IMs, and PMs were 1:5.3:13.1. Differences in the plasma gastrin levels (used as a PD marker) were also significant between the three groups and the increase was in an omeprazole-concentration-dependent fashion. Suitability of omeprazole as a probe for CYP2C19 was also explored. The metabolic ratio (MR) of omeprazole was correlated significantly with S/R ratio of mephenytoin.Paper II further studied the use of omeprazole as a probe for CYP2C19 activity in a population of 160 unrelated Swedish subjects. There was a close correlation between MRs of omeprazole and S/R ratios of mephenytoin. A good agreement was also demonstrated between the CYP2C19 phenotypes (both by omeprazole and mephenytoin) and the genotype with respect to CYP2C19*2, indicating that genotype is a valid predictor of CYP2C19 activity. Since omeprazole is a substrate for both CYP2C19 and CYP3A4, the potential advantage also includes using it as a dual-substrate probe.In Paper III, we used omeprazole as a dual substrate probe to assess the potential for PK interactions between carbamazepine (CBZ) and omeprazole and, particularly, the inducibility of CYP3A4 and CYP2C19 by CBZ. Both omeprazole and hydroxyomeprazole decreased by approximately 40% in mean AUC after coadministration of omeprazole with CBZ, while the sulphone metabolite increased by 44%. None of the AUC changes were statistically significant due to the large variation and small sample size. A significant decrease in the AUC ratio between hydroxyomeprazole and sulphone metabolite was observed, suggesting induction was more pronounced for CYP3A4 than for CYP2C19.The potential contribution of the CYP2C19 genotypes on R-warfarin clearance with special focus on the gain-of-function allele (CYP2C19*17) was the primary objective for Paper IV. Compared to CYP2C19*2 carriers, the mean R-warfarin clearance increased by 32% in CYP2C19*17 carriers, 26% in the CYP2C19*2/*17 genotype, and 11% in CYP2C19*1/*1 genotype. CYP2C19 genotypes also contributed to the variability of INR/daily dose where VKORC1 (Vitamin K epoxide reductase subcomplex 1) and CYP2C9 genotypes are the major determinants in warfarin treatment. About 52% of variance can be explained by the combinations of VKORC1, CYP2C9, CYP2C19, age, gender, and bodyweight, of which CYP2C19 genotypes accounted for 7%.Paper V pooled data from16 published studies to quantify the effect of functional CYP2C19 allele variants on citalopram/escitalopram exposure by means of meta-analysis. Compared to subjects with EM/EM (*1/*1) genotype, the exposure to (es)citalopram increased by 95% in the PM/PM (*2/*2, *2/*3, or *3/*3), 30% in the EM/PM (*1/*2 or *1/*3), and 25% in the UM (ultrarapid metaboliser)/PM (*17/*2 or *17/*3) groups. In contrast, the exposure to (es)citalopram decreased by 36% in the UM/UM (*17/*17) and by 14% in the UM/EM (*17/*1) groups. All functional CYP2C19 genotypes showed significant effects on citalopram/escitalopram exposure compared to the CYP2C19*1/*1 genotype.In conclusion, there are significant effects of CYP2C19 polymorphisms on PK and PD of drugs that are metabolized by the CYP2C19 enzyme. The results of this thesis demonstrate that CYP2C19 genotype is an important independent predictor of the exposure to omeprazole, R-warfarin, and citalopram/escitalopram. Increased knowledge and understanding of inter-individual variability, genotype-phenotype correlation, and the impact of CYP2C19 polymorphisms on clinical practice are helpful in optimizing personalized drug therapy." @default.
• W2158824094 created "2016-06-24" @default.
• W2158824094 creator A5027714312 @default.
• W2158824094 date "2014-11-13" @default.
• W2158824094 modified "2023-09-24" @default.
• W2158824094 title "CYP2C19 polymorphisms in drug metabolism and response" @default.
• W2158824094 cites W1502407336 @default.
• W2158824094 cites W1524323459 @default.
• W2158824094 cites W1550666015 @default.
• W2158824094 cites W1558332513 @default.
• W2158824094 cites W1560847265 @default.
• W2158824094 cites W1568940591 @default.
• W2158824094 cites W1583125800 @default.
• W2158824094 cites W1584188206 @default.
• W2158824094 cites W1587549092 @default.
• W2158824094 cites W1751541949 @default.
• W2158824094 cites W1781676997 @default.
• W2158824094 cites W1836343080 @default.
• W2158824094 cites W184350730 @default.
• W2158824094 cites W1898846685 @default.
• W2158824094 cites W1913784727 @default.
• W2158824094 cites W1915630750 @default.
• W2158824094 cites W1924733673 @default.
• W2158824094 cites W1927995536 @default.
• W2158824094 cites W1928423351 @default.
• W2158824094 cites W195154118 @default.
• W2158824094 cites W1967069400 @default.
• W2158824094 cites W1969825491 @default.
• W2158824094 cites W1969933572 @default.
• W2158824094 cites W1971306812 @default.
• W2158824094 cites W1973615600 @default.
• W2158824094 cites W1974969497 @default.
• W2158824094 cites W1975490782 @default.
• W2158824094 cites W1975793175 @default.
• W2158824094 cites W1979061109 @default.
• W2158824094 cites W1979157261 @default.
• W2158824094 cites W1979392961 @default.
• W2158824094 cites W1979646943 @default.
• W2158824094 cites W1980050671 @default.
• W2158824094 cites W1980779249 @default.
• W2158824094 cites W1980857267 @default.
• W2158824094 cites W1981202966 @default.
• W2158824094 cites W1983000301 @default.
• W2158824094 cites W1983220895 @default.
• W2158824094 cites W1983808878 @default.
• W2158824094 cites W1985059672 @default.
• W2158824094 cites W1985490286 @default.
• W2158824094 cites W1986064902 @default.
• W2158824094 cites W1986627308 @default.
• W2158824094 cites W1988853236 @default.
• W2158824094 cites W1991163272 @default.
• W2158824094 cites W1991886667 @default.
• W2158824094 cites W1992477076 @default.
• W2158824094 cites W1992633277 @default.
• W2158824094 cites W1993558201 @default.
• W2158824094 cites W1993717591 @default.
• W2158824094 cites W1995779830 @default.
• W2158824094 cites W1996411268 @default.
• W2158824094 cites W1997586764 @default.
• W2158824094 cites W1998388433 @default.
• W2158824094 cites W1998573208 @default.
• W2158824094 cites W1998622278 @default.
• W2158824094 cites W2000789841 @default.
• W2158824094 cites W2000791876 @default.
• W2158824094 cites W2005962512 @default.
• W2158824094 cites W2006537112 @default.
• W2158824094 cites W2008984280 @default.
• W2158824094 cites W2009386434 @default.
• W2158824094 cites W2010427019 @default.
• W2158824094 cites W2012156333 @default.
• W2158824094 cites W2012515901 @default.
• W2158824094 cites W2013135205 @default.
• W2158824094 cites W2013789360 @default.
• W2158824094 cites W2017472773 @default.
• W2158824094 cites W2017538702 @default.
• W2158824094 cites W2017589617 @default.
• W2158824094 cites W2018008180 @default.
• W2158824094 cites W2021333684 @default.
• W2158824094 cites W2021545207 @default.
• W2158824094 cites W2025392760 @default.
• W2158824094 cites W2028368615 @default.
• W2158824094 cites W2031202865 @default.
• W2158824094 cites W2036946450 @default.
• W2158824094 cites W2037289310 @default.
• W2158824094 cites W2037355442 @default.
• W2158824094 cites W2038028300 @default.
• W2158824094 cites W2039221921 @default.
• W2158824094 cites W2040735587 @default.
• W2158824094 cites W2041154771 @default.
• W2158824094 cites W2042292509 @default.
• W2158824094 cites W2044349089 @default.
• W2158824094 cites W2048111050 @default.
• W2158824094 cites W2049665672 @default.
• W2158824094 cites W2051903015 @default.
• W2158824094 cites W2053614573 @default.
• W2158824094 cites W2054023900 @default.
• W2158824094 cites W2056294728 @default.
• W2158824094 cites W2058444914 @default.
• W2158824094 cites W2060180669 @default.
• W2158824094 cites W2062323684 @default.

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