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Impact of CYP3A5 and P-glycoprotein ...

Huang, Weili.

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Impact of CYP3A5 and P-glycoprotein on hepatic and renal drug clearance.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Impact of CYP3A5 and P-glycoprotein on hepatic and renal drug clearance./
作者:	Huang, Weili.
面頁冊數:	201 p.
附註:	Adviser: Kenneth E. Thummel.
Contained By:	Dissertation Abstracts International67-11B.
標題:	Health Sciences, Pharmacy. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3241910
ISBN:	9780542978838

Impact of CYP3A5 and P-glycoprotein on hepatic and renal drug clearance.
Huang, Weili.

Impact of CYP3A5 and P-glycoprotein on hepatic and renal drug clearance. - 201 p.

Adviser: Kenneth E. Thummel.

Thesis (Ph.D.)--University of Washington, 2006.

Cytochrome P450 3A4 (CYP3A4) is the most abundant P450 enzyme in the liver and small intestine, where it plays a critical role in the metabolism of a great variety of xenobiotics and endogenous molecules. CYP3A5 is polymorphically expressed in human liver, intestine and kidney, sharing a broadly overlapping substrate profile with CYP3A4. The impact of the CYP3A5 polymorphism on variable drug clearance may be significant, but this remains a relatively understudied area.

ISBN: 9780542978838Subjects--Topical Terms:

1017737
Health Sciences, Pharmacy.

Impact of CYP3A5 and P-glycoprotein on hepatic and renal drug clearance.
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245 1 0 $a Impact of CYP3A5 and P-glycoprotein on hepatic and renal drug clearance.
300 $a 201 p.
500 $a Adviser: Kenneth E. Thummel.
500 $a Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6333.
502 $a Thesis (Ph.D.)--University of Washington, 2006.
520 $a Cytochrome P450 3A4 (CYP3A4) is the most abundant P450 enzyme in the liver and small intestine, where it plays a critical role in the metabolism of a great variety of xenobiotics and endogenous molecules. CYP3A5 is polymorphically expressed in human liver, intestine and kidney, sharing a broadly overlapping substrate profile with CYP3A4. The impact of the CYP3A5 polymorphism on variable drug clearance may be significant, but this remains a relatively understudied area.
520 $a In the first part of this dissertation, by utilizing recombinant enzymes and human liver microsomes (HLMs), we compared CYP3A4 and CYP3A5 biotransformation activity towards eight substrates, and found that CYP3A5 contributed significantly to the metabolism of flunitrazepam, midazolam and erythromycin.
520 $a This work was extended to evaluate the contribution of CYP3A5 to the metabolic clearance of an endogenous molecule, cortisol, in human liver and kidney. CYP3A5 is the only CYP3A enzyme expressed in human kidney. The CYP3A5 genotype is reported to be associated with susceptibility to hypertension, which may involve an alteration in the disposition of corticosteroids and their metabolites. In the second part and third parts of this dissertation, we described a new LC-MS/MS MRM procedure for the measurement of cortisol and its metabolites concentrations in human plasma and urine. We showed that, while CYP3A5 metabolizes cortisol, the CYP3A5 genotype does not appear to be a major determinant of hepatic and local renal cortisol disposition. Instead, cortisol disposition may be determined, in part by hepatic CYP3A4, and other renal enzymes and transporters.
520 $a In the fourth part of this dissertation, we confirmed that cortisol is transported by P-glycoprotein (P-gp), and in two clinical studies we found that hepatic CYP3A4-catalyzed cortisol metabolism and renal P-gp mediated cortisol clearance are inhibited by chronic ritonavir and itraconazole treatment. These pharmacokinetic effects were associated with an increase in plasma cortisol concentration that may contribute to adverse effects associated with long term use of protease inhibitors (PIs) and anti-fungal agents.
520 $a Together, these investigations showed that genetic and environmental factors contribute to inter-individual differences in CYP3A-dependent drug metabolism and P-gp mediated drug transport, affecting the safety and efficacy of therapeutic substrates/inhibitors for these proteins.
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791 $a Ph.D.
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