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Effect of genotype on CYP2C9 inhibition.

Kumar, Vikas.

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Effect of genotype on CYP2C9 inhibition.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Effect of genotype on CYP2C9 inhibition./
作者:	Kumar, Vikas.
面頁冊數:	200 p.
附註:	Adviser: Timothy S. Tracy.
Contained By:	Dissertation Abstracts International68-07B.
標題:	Health Sciences, Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3275050
ISBN:	9780549153214

Effect of genotype on CYP2C9 inhibition.
Kumar, Vikas.

Effect of genotype on CYP2C9 inhibition. - 200 p.

Adviser: Timothy S. Tracy.

Thesis (Ph.D.)--University of Minnesota, 2007.

Drug-drug interactions (DDI) occurring due to the inhibition of cytochrome P450 (CYP) enzymes may cause serious adverse events. The most abundant CYP2C isoform is CYP2C9.1, which is the major clearance pathway for the low therapeutic index drugs warfarin and phenytoin. Considering the importance of CYP2C9 to DDIs, accurate in vitro-in vivo extrapolation of DDI potential for CYP2C9 is critical. Unfortunately, this accuracy may be lessened via genotype- and substrate-dependent inhibition due to polymorphic variants and multiple binding sites of the CYP enzymes. Initially, a variety of recombinant CYP2C9 in vitro systems were investigated to determine the Michaelis-Menten kinetic parameters for four CYP2C9 substrates. The observed kinetic differences in metabolic product formation and intrinsic clearance were due to differences in the functional levels of redox partner enzymes and model membrane composition. Allelic variant dependent effects on naproxen metabolism by CYP2C9 and the resulting atypical kinetic profiles were then examined. Four amiodarone analogs were evaluated for differences in inhibition of CYP2C9.1 and CYP2C9.3. Analogs of amiodarone altered both the degree of naproxen turnover (activation or inhibition) and its atypical kinetic profile through effects on substrate binding and orientation. In addition, these kinetics effects were concentration- and genotype-dependent. Inhibition potency (Ki) studies using 28 effectors molecules with five commonly used probes of CYP2C9 were conducted with both CYP2C9.1 and CYP2C9.3 proteins to assess genotype dependent inhibition interactions. The inhibition of CYP2C9.1 and CYP2C9.3 by the battery of inhibitors demonstrated differential inhibition potency not only between the two genotypes but also, across substrate probes. Lastly to explore the clinical significance of genotype dependent CYP2C9 inhibition, a clinical study was conducted in individuals with no, one or two CYP2C9*3 alleles, using the probe drug flurbiprofen and the prototype CYP2C9 inhibitor fluconazole. The results demonstrated a genotype dependent inhibition of CYP2C9 in vivo. In conclusion, both genotype and choice of probe substrate must be considered when attempting to predict potential CYP2C9 DDIs from in vitro data. Also, genetic polymorphisms should be considered in determining the extent of inhibitory drug interactions in vivo.

ISBN: 9780549153214Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Effect of genotype on CYP2C9 inhibition.
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502 $a Thesis (Ph.D.)--University of Minnesota, 2007.
520 $a Drug-drug interactions (DDI) occurring due to the inhibition of cytochrome P450 (CYP) enzymes may cause serious adverse events. The most abundant CYP2C isoform is CYP2C9.1, which is the major clearance pathway for the low therapeutic index drugs warfarin and phenytoin. Considering the importance of CYP2C9 to DDIs, accurate in vitro-in vivo extrapolation of DDI potential for CYP2C9 is critical. Unfortunately, this accuracy may be lessened via genotype- and substrate-dependent inhibition due to polymorphic variants and multiple binding sites of the CYP enzymes. Initially, a variety of recombinant CYP2C9 in vitro systems were investigated to determine the Michaelis-Menten kinetic parameters for four CYP2C9 substrates. The observed kinetic differences in metabolic product formation and intrinsic clearance were due to differences in the functional levels of redox partner enzymes and model membrane composition. Allelic variant dependent effects on naproxen metabolism by CYP2C9 and the resulting atypical kinetic profiles were then examined. Four amiodarone analogs were evaluated for differences in inhibition of CYP2C9.1 and CYP2C9.3. Analogs of amiodarone altered both the degree of naproxen turnover (activation or inhibition) and its atypical kinetic profile through effects on substrate binding and orientation. In addition, these kinetics effects were concentration- and genotype-dependent. Inhibition potency (Ki) studies using 28 effectors molecules with five commonly used probes of CYP2C9 were conducted with both CYP2C9.1 and CYP2C9.3 proteins to assess genotype dependent inhibition interactions. The inhibition of CYP2C9.1 and CYP2C9.3 by the battery of inhibitors demonstrated differential inhibition potency not only between the two genotypes but also, across substrate probes. Lastly to explore the clinical significance of genotype dependent CYP2C9 inhibition, a clinical study was conducted in individuals with no, one or two CYP2C9*3 alleles, using the probe drug flurbiprofen and the prototype CYP2C9 inhibitor fluconazole. The results demonstrated a genotype dependent inhibition of CYP2C9 in vivo. In conclusion, both genotype and choice of probe substrate must be considered when attempting to predict potential CYP2C9 DDIs from in vitro data. Also, genetic polymorphisms should be considered in determining the extent of inhibitory drug interactions in vivo.
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