Inhibition of cytochrome P450 by ethambutol in human liver microsomes

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Title
Inhibition of cytochrome P450 by ethambutol in human liver microsomes
Author(s)
S Y Lee; H Jang; J Y Lee; K I Kwon; Soo Jin Oh; S K Kim
Bibliographic Citation
Toxicology Letters, vol. 229, no. 1, pp. 33-40
Publication Year
2014
Abstract
Although cytochrome P450 inhibition is the major drug-drug interaction (DDI) mechanism in clinical pharmacotherapy, DDI of a number of well-established drugs have not been investigated. Rifampicin, isoniazid, pyrazinamide and ethambutol combination therapy inhibits clearance of theophylline in patients with tuberculosis. We determined the inhibitory effects of ethambutol on the activities of nine CYP isoforms including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 in pooled human liver microsomes (HLM). As measured by liquid chromatography-electrospray ionization tandem mass spectrometry, ethambutol exhibited strong inhibitory potential against CYP1A2 and CYP2E1, moderate against CYP2C19 and CYP2D6 and weak against CYP2A6, CYP2C9 and CYP3A4, based on the IC50 values. The Ki value of ethambutol for CYP1A2 was 1.4μM and for CYP2E1 was 2.9μM. Inhibition of CYP1A2 and CYP2E1 was not increased by preincubation with ethambutol and β-nicotinamideadenine dinucleotide phosphate (NADPH), suggesting that the ethambutol-induced CYP inhibition may not be metabolism-dependent. Kinetic analysis showed that the inhibition of CYP1A2 and CYP2E1 by ethambutol was best fit to a competitive inhibition model. Formation of 1-methylxanthene and 1,3-dimethyluric acid from theophylline in HLM was decreased to 47% and 36%, respectively, by 3.0μM ethambutol, which is comparable to its IC50 value against CYP1A2. Considering its maximal plasma concentrations of ~10μM and long half-life of ~22h, our findings raise the possibility that ethambutol causes significant DDIs in clinical situations with drugs with narrow therapeutic index, such as theophylline, in clinical situations.
Keyword
CYP1A2CYP2E1EthambutolTheophyllineDrug-drug interaction
ISSN
0378-4274
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.toxlet.2014.06.006
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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