|
" פולימורפיזים גנטי בגן CYP2C9 ובפינוי המטבולי של וורפרין ופניטואין, מחקר באוכלוסייה בריאה ובחולים "
Shaul, Chanan
Caraco, Yoseph
| Document Type
|
:
|
Latin Dissertation
|
| Language of Document
|
:
|
English
|
| Record Number
|
:
|
1059109
|
| Doc. No
|
:
|
TL58226
|
| Main Entry
|
:
|
Shaul, Chanan
|
| Title & Author
|
:
|
פולימורפיזים גנטי בגן CYP2C9 ובפינוי המטבולי של וורפרין ופניטואין, מחקר באוכלוסייה בריאה ובחולים\ Shaul, ChananCaraco, Yoseph
|
| College
|
:
|
The Hebrew University of Jerusalem (Israel)
|
| Date
|
:
|
2019
|
| Degree
|
:
|
Ph.D.
|
| student score
|
:
|
2019
|
| Note
|
:
|
73 p.
|
| Abstract
|
:
|
Targeting of the narrow therapeutic index (NTI) drug warfarin is very challenging for patients and physicians alike. That's because subtherapeutic warfarin level can cause recurrence of the thromboembolic events while supratherapeutic level may significantly raise the bleeding risk. The initiation phase of warfarin's treatment is a critical period, characterized by fluctuations of patients' INR levels. It is well established that genetic factors, as well as environmental and other host factors, affect the individual response to warfarin through changes in the drug's pharmacokinetics (PK) and pharmacodynamics (PD). Genetic polymorphisms in CYP2C9, that mediates the metabolic clearance of (S)-warfarin (the more potent enantiomer of warfarin) accounts for the variability in the response to warfarin due to the drug's altered PK. Furthermore, variability in warfarin PD is partially attributed to genetic polymorphism in the target molecule (i.e. VKORC1) or in any of the coagulation factors including, for example, the coagulation factor VII. However, most of the information concerning inter-patient variability in response to warfarin was derived from cohorts of patients on chronic warfarin therapy (i.e. steady-state anticoagulation phase). In contrast, much less effort has been invested in the exploration of genetic and phenotypic markers that could predict the response to warfarin during the critical initiation period. Consequently, the objectives of my PhD thesis were as follows: 1) To provide an accurate quantitative estimate, among healthy subjects carrying different CYP2C9 genotypes, of (S)-warfarin oral clearance (CL/F) and (S)-warfarin formation clearance (CLf) to its CYP2C9-mediated metabolites, 6-hydroxy- and 7-hydroxy-(S)-warfarin. 2) To explore the influence of factor VII-genetic polymorphism-R353Q on the variability in the initial response to warfarin among healthy subjects. 3) To investigate if phenytoin, via its Phenytoin Metabolic Ratio (PMR), can serve as a phenotypic probe for (S)-warfarin clearance. The current study provides a quantitative estimate concerning the effect of CYP2C9 genetic polymorphism on (S)-warfarin PK as well as the effect of the impact of R353Q genetic polymorphism on factor VII activity and INR values during the initial period of warfarin treatment. PMR is a reliable marker of CYP2C9 activity in-vivo accounting for more than 30% of the variability in (S)-warfarin CL/F as well as (S)-warfarin CLf to its CYP2C9-mediated metabolites.
|
| Descriptor
|
:
|
Anticoagulants
|
|
|
:
|
Drug dosages
|
|
|
:
|
Drug interactions
|
|
|
:
|
Genetics
|
|
|
:
|
Genotype phenotype
|
|
|
:
|
Heart failure
|
|
|
:
|
Metabolism
|
|
|
:
|
Metabolites
|
|
|
:
|
Patients
|
|
|
:
|
Pharmaceutical sciences
|
|
|
:
|
Pharmacodynamics
|
|
|
:
|
Pharmacokinetics
|
|
|
:
|
Pharmacology
|
|
|
:
|
Physicians
|
|
|
:
|
Physiology
|
|
|
:
|
Plasma
|
|
|
:
|
Polymorphism
|
|
|
:
|
Precision medicine
|
|
|
:
|
Urine
|
| Added Entry
|
:
|
Caraco, Yoseph
|
| Added Entry
|
:
|
The Hebrew University of Jerusalem (Israel)
|
| |