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Vincristine metabolism and the role ...

Dennison, Jennifer Bolin.

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Vincristine metabolism and the role of CYP3A5.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Vincristine metabolism and the role of CYP3A5./
Author:	Dennison, Jennifer Bolin.
Description:	217 p.
Notes:	Adviser: Stephen D. Hall.
Contained By:	Dissertation Abstracts International68-11B.
Subject:	Chemistry, Pharmaceutical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3290771
ISBN:	9780549346630

Vincristine metabolism and the role of CYP3A5.
Dennison, Jennifer Bolin.

Vincristine metabolism and the role of CYP3A5. - 217 p.

Adviser: Stephen D. Hall.

Thesis (Ph.D.)--Indiana University, 2007.

Vincristine is metabolized by the cytochrome P450 3A subfamily of enzymes possibly including CYP3A5, a genetically polymorphic enzyme. The contribution of CYP3A5 to the metabolism of vincristine was quantified by various in vitro models: cDNA-expressed enzymes, human liver microsomes, and human hepatocytes. With these models, the major CYP metabolite of vincristine, M1, was identified and extensively characterized. The rates of M1 formation in the cDNA-expressed enzyme models were at least 7-fold higher with CYP3A5 than CYP3A4; approximately 90% of the hepatic metabolism was predicted to be CYP3A5-mediated. For human liver microsomes with high CYP3A5 expression, the CYP3A5 contribution was substantial, approximately 80%. Human hepatocytes with at least one CYP3A5*1 allele also metabolized vincristine, albeit at a slower rate (10-fold) than human liver microsomes. The CYP3A5 low-expressing hepatocytes did not metabolize vincristine. We conclude that for high CYP3A5 expressers, the majority of the CYP metabolism is mediated by CYP3A5. By in vitro/in vivo scaling with microsomes, the hepatic clearances of high CYP3A5 expressers are predicted to have a 5-fold higher hepatic clearance than low expressers. However, the role of metabolism in the systemic clearance of vincristine is unknown. To study the disposition of vincristine in vivo, a sensitive and selective LC/MS/MS assay was validated for the quantification of vincristine and M1 quantification in human plasma. Vincristine and M1 were identified and quantified in select pediatric plasma and urine samples. For future large-scale clinical studies, the vincristine and M1 concentrations in plasma will be quantified to understand the role of CYP3A5 genotype in vincristine pharmacokinetics. For patients that are CYP3A5 high expressers, the systemic clearance of vincristine may be higher than that of low CYP3A5 expressers. Thus, CYP3A5 genotype may be an important determinant of inter-individual variability in clinical outcomes.

ISBN: 9780549346630Subjects--Topical Terms:

550957
Chemistry, Pharmaceutical.

Vincristine metabolism and the role of CYP3A5.
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020 $a 9780549346630
035 $a (UMI)AAI3290771
035 $a AAI3290771
040 $a UMI $c UMI
100 1 $a Dennison, Jennifer Bolin. $3 1262937
245 1 0 $a Vincristine metabolism and the role of CYP3A5.
300 $a 217 p.
500 $a Adviser: Stephen D. Hall.
500 $a Source: Dissertation Abstracts International, Volume: 68-11, Section: B, page: 7270.
502 $a Thesis (Ph.D.)--Indiana University, 2007.
520 $a Vincristine is metabolized by the cytochrome P450 3A subfamily of enzymes possibly including CYP3A5, a genetically polymorphic enzyme. The contribution of CYP3A5 to the metabolism of vincristine was quantified by various in vitro models: cDNA-expressed enzymes, human liver microsomes, and human hepatocytes. With these models, the major CYP metabolite of vincristine, M1, was identified and extensively characterized. The rates of M1 formation in the cDNA-expressed enzyme models were at least 7-fold higher with CYP3A5 than CYP3A4; approximately 90% of the hepatic metabolism was predicted to be CYP3A5-mediated. For human liver microsomes with high CYP3A5 expression, the CYP3A5 contribution was substantial, approximately 80%. Human hepatocytes with at least one CYP3A5*1 allele also metabolized vincristine, albeit at a slower rate (10-fold) than human liver microsomes. The CYP3A5 low-expressing hepatocytes did not metabolize vincristine. We conclude that for high CYP3A5 expressers, the majority of the CYP metabolism is mediated by CYP3A5. By in vitro/in vivo scaling with microsomes, the hepatic clearances of high CYP3A5 expressers are predicted to have a 5-fold higher hepatic clearance than low expressers. However, the role of metabolism in the systemic clearance of vincristine is unknown. To study the disposition of vincristine in vivo, a sensitive and selective LC/MS/MS assay was validated for the quantification of vincristine and M1 quantification in human plasma. Vincristine and M1 were identified and quantified in select pediatric plasma and urine samples. For future large-scale clinical studies, the vincristine and M1 concentrations in plasma will be quantified to understand the role of CYP3A5 genotype in vincristine pharmacokinetics. For patients that are CYP3A5 high expressers, the systemic clearance of vincristine may be higher than that of low CYP3A5 expressers. Thus, CYP3A5 genotype may be an important determinant of inter-individual variability in clinical outcomes.
590 $a School code: 0093.
650 4 $a Chemistry, Pharmaceutical. $3 550957
650 4 $a Health Sciences, Pharmacology. $3 1017717
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710 2 0 $a Indiana University. $b Pharmacology & Toxicology. $3 1262938
773 0 $t Dissertation Abstracts International $g 68-11B.
790 $a 0093
790 1 0 $a Erickson, Leonard C. $e committee member
790 1 0 $a Hall, Stephen D., $e advisor
790 1 0 $a Kamendulis, Lisa M. $e committee member
790 1 0 $a Queener, Sherry F. $e committee member
790 1 0 $a Wrighton, Steven A. $e committee member
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3290771