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Explanation through density functional theory of the unanticipated loss of CO 2 and differences in mass fragmentation profiles of ritonavir and its rCYP3A4‐mediated metabolites
Author(s) -
Jhajra Shalu,
Handa Tarun,
Bhatia Sonam,
Bharatam P. V.,
Singh Saranjit
Publication year - 2014
Publication title -
journal of mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 121
eISSN - 1096-9888
pISSN - 1076-5174
DOI - 10.1002/jms.3359
Subject(s) - chemistry , fragmentation (computing) , moiety , metabolite , ritonavir , density functional theory , stereochemistry , chromatography , medicinal chemistry , computational chemistry , biochemistry , human immunodeficiency virus (hiv) , medicine , family medicine , computer science , antiretroviral therapy , viral load , operating system
In the present study, the metabolism of ritonavir was explored in the presence of rCYP3A4 using a well‐established strategy involving liquid chromatography–mass spectrometry (LC–MS) tools. A total of six metabolites were formed, of which two were new, not reported earlier as CYP3A4‐mediated metabolites. During LC–MS studies, ritonavir was found to fragment through six principal pathways, many of which involved neutral loss of CO 2 , as indicated through 44‐Da difference between masses of the precursors and the product ions. This was unusual as the drug and the precursors were devoid of a terminal carboxylic acid group. Apart from the neutral loss of CO 2 , marked differences were also observed among the fragmentation pathways of the drug and its metabolites having intact N ‐methyl moiety as compared to those lacking N ‐methyl moiety. These unusual fragmentation behaviours were successfully explained through energy distribution profiles by application of the density functional theory. Copyright © 2014 John Wiley & Sons, Ltd.