CYP2C19 polymorphisms in drug metabolism and response

摘要: Individuals vary widely in their response to drug treatment. After receiving doses of a that are recommended based on population average, some patients could have an insufficient response, whereas others may experience adverse effects. Of the many factors causing variability across individuals, genetic polymorphism drug-metabolizing enzymes is deemed be one valuable independent predictors this variability. CYP2C19 important polymorphically expressed enzyme known catalyze metabolism several prescribed drugs, including omeprazole, warfarin (R-enantiomer), and citalopram/escitalopram. The impact polymorphisms pharmacokinetics (PK) its substrates corresponding clinical relevance great interest. The aim thesis investigate influence PK pharmacodynamics (PD) clinically (e.g., citalopram, warfarin), advance understanding inter-individual therapy. We quantified effect functional allele variants, gain-of- function (CYP2C19*17), exposure order facilitate personalized dose selection. In Paper I, we studied disposition omeprazole plasma gastrin levels following single multiple three phenotype groups (extensive metabolisers [EMs], intermediate [IMs], poor [PMs]) S- mephenytoin hydroxylation. When 20 mg was given orally for 8 days once-daily (QD) regimen, relative AUC ratios EMs, IMs, PMs were 1:5.3:13.1. Differences (used as PD marker) also significant between increase omeprazole-concentration-dependent fashion. Suitability probe explored. metabolic ratio (MR) correlated significantly with S/R mephenytoin. Paper II further use activity 160 unrelated Swedish subjects. There close correlation MRs mephenytoin. A good agreement demonstrated phenotypes (both by mephenytoin) genotype respect CYP2C19*2, indicating valid predictor activity. Since substrate both CYP3A4, potential advantage includes using it dual-substrate probe. In III, used dual assess interactions carbamazepine (CBZ) and, particularly, inducibility CYP3A4 CBZ. Both hydroxyomeprazole decreased approximately 40% mean after coadministration CBZ, while sulphone metabolite increased 44%. None changes statistically due large variation small sample size. decrease observed, suggesting induction more pronounced than CYP2C19. The contribution genotypes R-warfarin clearance special focus gain-of-function (CYP2C19*17) primary objective IV. Compared CYP2C19*2 carriers, 32% CYP2C19*17 26% CYP2C19*2/*17 genotype, 11% CYP2C19*1/*1 genotype. contributed INR/daily where VKORC1 (Vitamin K epoxide reductase subcomplex 1) CYP2C9 major determinants About 52% variance can explained combinations VKORC1, CYP2C9, CYP2C19, age, gender, bodyweight, which accounted 7%. Paper V pooled data from16 published studies quantify variants citalopram/escitalopram means meta-analysis. subjects EM/EM (*1/*1) (es)citalopram 95% PM/PM (*2/*2, *2/*3, or *3/*3), 30% EM/PM (*1/*2 *1/*3), 25% UM (ultrarapid metaboliser)/PM (*17/*2 *17/*3) groups. In contrast, 36% UM/UM (*17/*17) 14% UM/EM (*17/*1) All showed effects compared genotype. In conclusion, there drugs metabolized enzyme. results demonstrate R-warfarin, Increased knowledge variability, genotype-phenotype correlation, practice helpful optimizing