| Potential contribution of cytochrome P450 2B6 to hepatic 4-hydroxycyclophosphamide formation in vitro and in vivo. | |
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MedLine Citation:
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PMID: 21976622 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Results from retrospective studies on the relationship between cytochrome P450 (P450) 2B6 (CYP2B6) genotype and cyclophosphamide (CY) efficacy and toxicity in adult cancer patients have been conflicting. We evaluated this relationship in children, who have faster CY clearance and receive different CY-based regimens than adults. These factors may influence the P450s metabolizing CY to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. Therefore, we sought to characterize the in vitro and in vivo roles of hepatic CYP2B6 and its main allelic variants in 4HCY formation. CYP2B6 is the major isozyme responsible for 4HCY formation in recombinant P450 Supersomes. In human liver microsomes (HLM), 4HCY formation correlated with known phenotypic markers of CYP2B6 activity, specifically formation of (S)-2-ethyl-1,5-dimethyl-3,3-diphenyl pyrrolidine and hydroxybupropion. However, in HLM, CYP3A4/5 also contributes to 4HCY formation at the CY concentrations similar to plasma concentrations achieved in children (0.1 mM). 4HCY formation was not associated with CYP2B6 genotype at low (0.1 mM) or high (1 mM) CY concentrations potentially because CYP3A4/5 and other isozymes also form 4HCY. To remove this confounder, 4HCY formation was evaluated in recombinant CYP2B6 enzymes, which demonstrated that 4HCY formation was lower for CYP2B6.4 and CYP2B6.5 compared with CYP2B6.1. In vivo, CYP2B6 genotype was not directly related to CY clearance or ratio of 4HCY/CY areas under the curve in 51 children receiving CY-based regimens. Concomitant chemotherapy agents did not influence 4HCY formation in vitro. We conclude that CYP2B6 genotype is not consistently related to 4HCY formation in vitro or in vivo. |
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Authors:
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Brianne S Raccor; Adam J Claessens; Jean C Dinh; Julie R Park; Douglas S Hawkins; Sushma S Thomas; Karen W Makar; Jeannine S McCune; Rheem A Totah |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-10-05 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 40 ISSN: 1521-009X ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2011-12-19 Completed Date: 2012-08-31 Revised Date: 2013-02-20 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 54-63 Citation Subset: IM |
Affiliation:
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Department of Pharmacy, University of Washington, Seattle, WA 98195-7610, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adolescent Aryl Hydrocarbon Hydroxylases / genetics*, metabolism* Child Child, Preschool Cyclophosphamide / analogs & derivatives*, metabolism, pharmacology Genetic Variation / genetics* Humans Infant Microsomes, Liver / drug effects, enzymology, metabolism* Oxidoreductases, N-Demethylating / genetics*, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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M01-RR00037/RR/NCRR NIH HHS; P01-GM032165/GM/NIGMS NIH HHS; R01-HL91744S1/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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40277-05-2/4-hydroxycyclophosphamide; 50-18-0/Cyclophosphamide; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/S-mephenytoin N-demethylase; EC 1.5.-/Oxidoreductases, N-Demethylating |
| Comments/Corrections | |
Comment In:
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Drug Metab Dispos. 2012 Mar;40(3):635-7
[PMID:
22159699
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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