Bioactivation of a novel 2-methylindole-containing dual chemoattractant receptor-homologous molecule expressed on T-helper type-2 cells/D-prostanoid receptor antagonist leads to mechanism-based CYP3A inactivation: glutathione adduct characterization and prediction of in vivo drug-drug interaction.
The 2-methyl substituted indole, 2MI [2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1H-indol-5-yloxy)-3-methoxyphenyl)acetic acid] is a potent dual inhibitor of 1) chemoattractant receptor-homologous molecule expressed on T-helper type-2 cells and 2) d-prostanoid receptor. During evaluation as a potential treatment for asthma and allergic rhinitis, 2MI was identified as a mechanism-based inactivator of CYP3A4 in vitro. The inactivation was shown to be irreversible by dialysis and accompanied by an NADPH-dependent increase in 2MI covalent binding to a 55- to 60-kDa microsomal protein, consistent with irreversible binding to CYP3A4. Two glutathione (GSH) adducts, G1 and G2, were identified in vitro, and the more abundant adduct (G1) was unambiguously determined via NMR to be GSH adducted to the 3-position of the 2-methylindole moiety. The potential for a clinical drug-drug interaction arising from mechanism-based inactivation of CYP3A4 by 2MI was predicted using a steady-state model, and a 4.3- to 7.5-fold increase in the exposure of midazolam was predicted at anticipated therapeutic concentrations. To better assess the potential for in vivo drug-drug interactions, the Sprague-Dawley rat was used as an in vivo model. An excellent in vitro-in vivo correlation was observed for the reduction in enzyme steady-state concentration (E'(ss/Ess)) as well as the change in the exposure of a prototypical CYP3A substrate, indinavir (area under the curve (AUC) for indinavir/AUC). In summary, 2MI was identified as a potent mechanism-based inactivator of CYP3A and was predicted to elicit a clinically relevant drug-drug interaction in humans at an anticipated therapeutic concentration.
Wong
Simon G
SG
Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA. simon.wong@amgen.com
Fan
Peter W
PW
Subramanian
Raju
R
Tonn
George R
GR
Henne
Kirk R
KR
Johnson
Michael G
MG
Tadano Lohr
Michelle
M
Wong
Bradley K
BK
D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D055162:Biocatalysis / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism*; D006735:Horseradish Peroxidase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019469:Indinavir / Q000378:metabolism / Q000493:pharmacokinetics; D007211:Indoles / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism / Q000493:pharmacokinetics; D008954:Models, Biological; D015394:Molecular Structure; D009249:NADP / Q000378:metabolism; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry
D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D009249:NADP; D019469:Indinavir; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005978:Glutathione; D008874:Midazolam; C036293:prostaglandin D2 receptor