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Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib.
Drug Metab Dispos. 2005 Nov; 33(11):1723-8.DM

Abstract

VELCADE (bortezomib, PS-341), reversibly inhibits the 20S proteasome and exhibits cytotoxic and antitumor activities. Pretreatment of cancer cells with bortezomib increases the chemosensitivity of these cells, suggesting that bortezomib may be used in combination chemotherapy. The relative contributions of the five major human cytochromes P450 (P450s), 1A2, 2C9, 2C19, 2D6, and 3A4 (the focus of the present study), to the metabolism of bortezomib are an important aspect of potential drug interactions. Relative activity factor (RAF), chemical inhibition, and immunoinhibition using monoclonal antibodies were three approaches employed to determine the relative contributions of the major human P450s to the net hepatic metabolism of bortezomib. RAFs for the P450 isoform-selective substrates were determined; the ratio of the rate of metabolism of bortezomib with cDNA-expressed P450s versus rate of metabolism with human liver microsomes was normalized with respect to the RAF for each P450 isoform to determine the percentage contributions of the P450s to the net hepatic metabolism of bortezomib. CYP3A4 followed by CYP2C19 were determined to be the major contributors to the metabolism of bortezomib. Chemical inhibition and immunoinhibition confirmed that CYP3A4 and CYP2C19 were the major P450s responsible for the hepatic metabolism of bortezomib. The studies were conducted with 2 muM bortezomib, and the disappearance of bortezomib, rather than appearance of a specific metabolite, was quantified to determine the contributions of the P450s to the overall hepatic metabolism of bortezomib in humans.

Authors+Show Affiliations

Department of Drug Metabolism and Pharmacokinetics, Drug Safety and Disposition, Millennium Pharmaceuticals, Cambridge, MA 02139, USA. vinita.uttamsingh@mpi.comNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

16103134

Citation

Uttamsingh, Vinita, et al. "Relative Contributions of the Five Major Human Cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the Hepatic Metabolism of the Proteasome Inhibitor Bortezomib." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 33, no. 11, 2005, pp. 1723-8.
Uttamsingh V, Lu C, Miwa G, et al. Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos. 2005;33(11):1723-8.
Uttamsingh, V., Lu, C., Miwa, G., & Gan, L. S. (2005). Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 33(11), 1723-8.
Uttamsingh V, et al. Relative Contributions of the Five Major Human Cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the Hepatic Metabolism of the Proteasome Inhibitor Bortezomib. Drug Metab Dispos. 2005;33(11):1723-8. PubMed PMID: 16103134.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. AU - Uttamsingh,Vinita, AU - Lu,Chuang, AU - Miwa,Gerald, AU - Gan,Liang-Shang, Y1 - 2005/08/15/ PY - 2005/8/17/pubmed PY - 2006/8/5/medline PY - 2005/8/17/entrez SP - 1723 EP - 8 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 33 IS - 11 N2 - VELCADE (bortezomib, PS-341), reversibly inhibits the 20S proteasome and exhibits cytotoxic and antitumor activities. Pretreatment of cancer cells with bortezomib increases the chemosensitivity of these cells, suggesting that bortezomib may be used in combination chemotherapy. The relative contributions of the five major human cytochromes P450 (P450s), 1A2, 2C9, 2C19, 2D6, and 3A4 (the focus of the present study), to the metabolism of bortezomib are an important aspect of potential drug interactions. Relative activity factor (RAF), chemical inhibition, and immunoinhibition using monoclonal antibodies were three approaches employed to determine the relative contributions of the major human P450s to the net hepatic metabolism of bortezomib. RAFs for the P450 isoform-selective substrates were determined; the ratio of the rate of metabolism of bortezomib with cDNA-expressed P450s versus rate of metabolism with human liver microsomes was normalized with respect to the RAF for each P450 isoform to determine the percentage contributions of the P450s to the net hepatic metabolism of bortezomib. CYP3A4 followed by CYP2C19 were determined to be the major contributors to the metabolism of bortezomib. Chemical inhibition and immunoinhibition confirmed that CYP3A4 and CYP2C19 were the major P450s responsible for the hepatic metabolism of bortezomib. The studies were conducted with 2 muM bortezomib, and the disappearance of bortezomib, rather than appearance of a specific metabolite, was quantified to determine the contributions of the P450s to the overall hepatic metabolism of bortezomib in humans. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/16103134/Relative_contributions_of_the_five_major_human_cytochromes_P450_1A2_2C9_2C19_2D6_and_3A4_to_the_hepatic_metabolism_of_the_proteasome_inhibitor_bortezomib_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16103134 DB - PRIME DP - Unbound Medicine ER -