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Cancer Chemotherapy and Pharmacology

Published in:

01-01-2012 | Original Article

In vitro assessment of cytochrome P450 inhibition and induction potential of tanespimycin and its major metabolite, 17-amino-17-demethoxygeldanamycin

Authors: Jinping Gan, Peggy Liu-Kreyche, W. Griffith Humphreys

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2012

Abstract

Purpose

To assess the inhibition and induction potential of tanespimycin and its major metabolite, 17-amino-17-demethoxygeldanamycin (17-AG) on cytochrome P450 (CYP) enzymes.

Methods

The inhibitory effect of tanespimycin and 17-AG on various CYP enzymes was determined in human liver microsomes. The inductive effects of tanespimycin and 17-AG on CYP1A2, CYP2B6, and CYP3A4/5 were determined in cultured primary human hepatocytes.

Results

Tanespimycin did not inhibit the activities of CYP1A2, 2A6, 2B6, and 2E1 up to a concentration of 60 μM, while it moderately inhibited CYP3A4/5 and 2C19, and weakly inhibited CYP2C8, 2C9, and 2D6. In addition, its inhibition on CYP3A4/5 was time-dependent. 17-AG moderately inhibited the activities of CYP3A4/5 and CYP2C19, but did not inhibit other CYPs up to a concentration of 30 μM. The inhibition of CYP3A4/5 by 17-AG was not time-dependent. Tanespimycin and 17-AG did not significantly induce the activities of CYP1A2, CYP2B6, or CYP3A4/5 in cultured human hepatocytes at concentrations up to 40 and 20 μM for tanespimycin and 17-AG, respectively.

Conclusions

Tanespimycin together with its active metabolite, 17-AG are moderate inhibitors of CYP3A4/5 and CYP2C19, but not inducers of CYPs. Therefore, co-administration of tanespimycin has the potential to increase the exposure of substrates of CYP2C19 and CYP3A4/5.

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Title: In vitro assessment of cytochrome P450 inhibition and induction potential of tanespimycin and its major metabolite, 17-amino-17-demethoxygeldanamycin
Authors: Jinping Gan
Peggy Liu-Kreyche
W. Griffith Humphreys
Publication date: 01-01-2012
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1672-2

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Abstract

Purpose

Methods

Results

Conclusions

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