Inhibition of cytochrome P450 by ethambutol in human liver microsomes.

Article Details

Citation

Lee SY, Jang H, Lee JY, Kwon KI, Oh SJ, Kim SK

Inhibition of cytochrome P450 by ethambutol in human liver microsomes.

Toxicol Lett. 2014 Aug 17;229(1):33-40. doi: 10.1016/j.toxlet.2014.06.006. Epub 2014 Jun 5.

PubMed ID
24910189 [ View in PubMed
]
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 K(i) value of ethambutol for CYP1A2 was 1.4 muM and for CYP2E1 was 2.9 muM. Inhibition of CYP1A2 and CYP2E1 was not increased by preincubation with ethambutol and beta-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 3.0 muM ethambutol, which is comparable to its IC50 value against CYP1A2. Considering its maximal plasma concentrations of ~10 muM and long half-life of ~22 h, 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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
EthambutolCytochrome P450 1A2ProteinHumans
Unknown
Inhibitor
Details
EthambutolCytochrome P450 2A6ProteinHumans
Unknown
Inhibitor
Details
EthambutolCytochrome P450 2C19ProteinHumans
Unknown
Inhibitor
Details
EthambutolCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
EthambutolCytochrome P450 2D6ProteinHumans
Unknown
Inhibitor
Details
EthambutolCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details
EthambutolCytochrome P450 3A4ProteinHumans
Unknown
Inhibitor
Details