FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4380051363> ?p ?o ?g. }

• W4380051363 abstract "Introduction: Pharmacogenetics-informed drug prescribing is increasingly applied in clinical practice. Typically, drug metabolizing phenotypes are determined based on genetic test results, whereupon dosage or drugs are adjusted. Drug-drug-interactions (DDIs) caused by concomitant medication can however cause mismatches between predicted and observed phenotypes (phenoconversion). Here we investigated the impact of CYP2C19 genotype on the outcome of CYP2C19-dependent DDIs in human liver microsomes. Methods: Liver samples from 40 patients were included, and genotyped for CYP2C19 *2, *3 and *17 variants. S-mephenytoin metabolism in microsomal fractions was used as proxy for CYP2C19 activity, and concordance between genotype-predicted and observed CYP2C19 phenotype was examined. Individual microsomes were subsequently co-exposed to fluvoxamine, voriconazole, omeprazole or pantoprazole to simulate DDIs. Results: Maximal CYP2C19 activity (V max ) in genotype-predicted intermediate metabolizers (IMs; *1/*2 or *2/*17), rapid metabolizers (RMs; *1/*17) and ultrarapid metabolizers (UMs; *17/*17) was not different from V max of predicted normal metabolizers (NMs; *1/*1). Conversely, CYP2C19 *2/*2 genotyped-donors exhibited V max rates ∼9% of NMs, confirming the genotype-predicted poor metabolizer (PM) phenotype. Categorizing CYP2C19 activity, we found a 40% concordance between genetically-predicted CYP2C19 phenotypes and measured phenotypes, indicating substantial phenoconversion. Eight patients (20%) exhibited CYP2C19 IM/PM phenotypes that were not predicted by their CYP2C19 genotype, of which six could be linked to the presence of diabetes or liver disease. In subsequent DDI experiments, CYP2C19 activity was inhibited by omeprazole (−37% ± 8%), voriconazole (−59% ± 4%) and fluvoxamine (−85% ± 2%), but not by pantoprazole (−2 ± 4%). The strength of CYP2C19 inhibitors remained unaffected by CYP2C19 genotype, as similar percental declines in CYP2C19 activity and comparable metabolism-dependent inhibitory constants (K inact /K I ) of omeprazole were observed between CYP2C19 genotypes. However, the consequences of CYP2C19 inhibitor-mediated phenoconversion were different between CYP2C19 genotypes. In example, voriconazole converted 50% of *1/*1 donors to a IM/PM phenotype, but only 14% of *1/*17 donors. Fluvoxamine converted all donors to phenotypic IMs/PMs, but *1/*17 (14%) were less likely to become PMs than *1/*1 (50%) or *1/*2 and *2/*17 (57%). Conclusion: This study suggests that the differential outcome of CYP2C19-mediated DDIs between genotypes are primarily dictated by basal CYP2C19 activity, that may in part be predicted by CYP2C19 genotype but likely also depends on disease-related factors." @default.
• W4380051363 created "2023-06-10" @default.
• W4380051363 creator A5003028700 @default.
• W4380051363 creator A5026554824 @default.
• W4380051363 creator A5028880756 @default.
• W4380051363 creator A5036385467 @default.
• W4380051363 creator A5060111407 @default.
• W4380051363 creator A5060562733 @default.
• W4380051363 creator A5063768298 @default.
• W4380051363 creator A5073070631 @default.
• W4380051363 creator A5079927892 @default.
• W4380051363 creator A5092126553 @default.
• W4380051363 date "2023-06-08" @default.
• W4380051363 modified "2023-09-25" @default.
• W4380051363 title "The impact of CYP2C19 genotype on phenoconversion by concomitant medication" @default.
• W4380051363 cites W1536291316 @default.
• W4380051363 cites W1577577364 @default.
• W4380051363 cites W1804639872 @default.
• W4380051363 cites W2010427019 @default.
• W4380051363 cites W2020744962 @default.
• W4380051363 cites W2033644570 @default.
• W4380051363 cites W2054678290 @default.
• W4380051363 cites W2060724453 @default.
• W4380051363 cites W2064447549 @default.
• W4380051363 cites W2082160386 @default.
• W4380051363 cites W2104021816 @default.
• W4380051363 cites W2114643090 @default.
• W4380051363 cites W2114767218 @default.
• W4380051363 cites W2127752492 @default.
• W4380051363 cites W2136015626 @default.
• W4380051363 cites W2136695358 @default.
• W4380051363 cites W2143550409 @default.
• W4380051363 cites W2148166921 @default.
• W4380051363 cites W2150287431 @default.
• W4380051363 cites W2155690985 @default.
• W4380051363 cites W2161620765 @default.
• W4380051363 cites W2166861655 @default.
• W4380051363 cites W2224177558 @default.
• W4380051363 cites W2552645335 @default.
• W4380051363 cites W2565800883 @default.
• W4380051363 cites W2605348885 @default.
• W4380051363 cites W2612709423 @default.
• W4380051363 cites W2752618943 @default.
• W4380051363 cites W2756738310 @default.
• W4380051363 cites W2771950797 @default.
• W4380051363 cites W2789160819 @default.
• W4380051363 cites W2804079128 @default.
• W4380051363 cites W2889846990 @default.
• W4380051363 cites W2892026465 @default.
• W4380051363 cites W2895848630 @default.
• W4380051363 cites W2912847294 @default.
• W4380051363 cites W2943321910 @default.
• W4380051363 cites W2944956458 @default.
• W4380051363 cites W3047884069 @default.
• W4380051363 cites W3083299599 @default.
• W4380051363 cites W3091888242 @default.
• W4380051363 cites W3112424423 @default.
• W4380051363 cites W3114326816 @default.
• W4380051363 cites W3158869533 @default.
• W4380051363 cites W3184746188 @default.
• W4380051363 cites W3193348699 @default.
• W4380051363 cites W3202722236 @default.
• W4380051363 cites W4207040168 @default.
• W4380051363 cites W4220722277 @default.
• W4380051363 cites W4280492437 @default.
• W4380051363 cites W4281652467 @default.
• W4380051363 cites W4283704422 @default.
• W4380051363 cites W4319063488 @default.
• W4380051363 doi "https://doi.org/10.3389/fphar.2023.1201906" @default.
• W4380051363 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37361233" @default.
• W4380051363 hasPublicationYear "2023" @default.
• W4380051363 type Work @default.
• W4380051363 citedByCount "0" @default.
• W4380051363 crossrefType "journal-article" @default.
• W4380051363 hasAuthorship W4380051363A5003028700 @default.
• W4380051363 hasAuthorship W4380051363A5026554824 @default.
• W4380051363 hasAuthorship W4380051363A5028880756 @default.
• W4380051363 hasAuthorship W4380051363A5036385467 @default.
• W4380051363 hasAuthorship W4380051363A5060111407 @default.
• W4380051363 hasAuthorship W4380051363A5060562733 @default.
• W4380051363 hasAuthorship W4380051363A5063768298 @default.
• W4380051363 hasAuthorship W4380051363A5073070631 @default.
• W4380051363 hasAuthorship W4380051363A5079927892 @default.
• W4380051363 hasAuthorship W4380051363A5092126553 @default.
• W4380051363 hasBestOaLocation W43800513631 @default.
• W4380051363 hasConcept C104317684 @default.
• W4380051363 hasConcept C126322002 @default.
• W4380051363 hasConcept C135763542 @default.
• W4380051363 hasConcept C140840227 @default.
• W4380051363 hasConcept C2777498785 @default.
• W4380051363 hasConcept C33664856 @default.
• W4380051363 hasConcept C526171541 @default.
• W4380051363 hasConcept C54355233 @default.
• W4380051363 hasConcept C55775858 @default.
• W4380051363 hasConcept C62231903 @default.
• W4380051363 hasConcept C71924100 @default.
• W4380051363 hasConcept C86803240 @default.
• W4380051363 hasConcept C98274493 @default.
• W4380051363 hasConceptScore W4380051363C104317684 @default.
• W4380051363 hasConceptScore W4380051363C126322002 @default.

• next