Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes.

Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Research Abstract Details 

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Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Abstract Text:

Jing Li,Ming Zhao,Ping He,Manuel Hidalgo,Sharyn D Baker,

PURPOSE: To examine the enzyme kinetics of gefitinib and erlotinib metabolism by individual cytochrome P450 (CYP) enzymes, and to compare their effects on CYP3A activity, with the aim to better understand mechanisms underlying pharmacokinetic variability and clinical effects. EXPERIMENTAL DESIGN: Enzyme kinetics were examined by incubating gefitinib or erlotinib (1.5-50 micromol/L) with recombinant human CYP3A4, CYP3A5, CYP2D6, CYP1A1, CYP1A2, and CYP1B1 (10-160 pmol/mL). Their effects on CYP3A activity were examined by comparing midazolam metabolism in the presence and absence of gefitinib or erlotinib in human liver and intestinal microsomes. Parent compounds and metabolites were monitored by high-performance liquid chromatography with a photodiode detector or tandem mass spectrometer. RESULTS: Both drugs were metabolized primarily by CYP3A4, CYP3A5, and CYP1A1, with respective maximum clearance (Cl(max)) values for metabolism of 0.41, 0.39, and 0.57 mL/min/nmol for gefitinib and 0.24, 0.21, 0.31 mL/min/nmol for erlotinib. CYP2D6 was involved in gefitinib metabolism (Cl(max), 0.63 mL/min/nmol) to a large extent, whereas CYP1A2 was considerably involved in erlotinib metabolism (Cl(max), 0.15 mL/min/nmol). Both drugs stimulated CYP3A-mediated midazolam disappearance and 1-hydroxymidazolam formation in liver and intestinal microsomes. CONCLUSIONS: Gefitinib is more susceptible to CYP3A-mediated metabolism than erlotinib, which may contribute to the higher apparent oral clearance observed for gefitinib. Metabolism by hepatic and extrahepatic CYP1A may represent a determinant of pharmacokinetic variability and response for both drugs. The differential metabolizing enzyme profiles suggest that there may be differences in drug-drug interaction potential and that stimulation of CYP3A4 may likely play a role in drug interactions for erlotinib and gefitinib.

Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Publishing Authors By Initials

J Li,M Zhao,P He,M Hidalgo,SD Baker,

For similar proteins: recombinant proteins research abstracts see: proteins: recombinant proteins research

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Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Clinical cancer research : an official journal of

VOLUME: 13

Page Numbers: 3731-7

Journal Abbreviation: Clin. Cancer Res.

ISSN: 1078-0432

DAY: 15

MONTH: Jun

YEAR: 2007

Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9502500

Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Keywords Mesh Terms:

KEYWORDS: Recombinant Proteins

MESH TERMS: metabolism

Chemical & Substance for Abstract: Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Information

Substance Name: Cytochrome P-450 Enzyme System

Registry Number: 9035-51-2

Grant and Affiliation Information for Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes.

AFFILIATION: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.

Country: United States

AGENCY: United States NCCAM

GRANT: P50 AT00437

ACRONYM: AT

MEDLINETA: Clin Cancer Res

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