Characterization of bropirimine O-glucuronidation in human liver microsomes

1. The antitumour agent bropirimine undergoes significant Phase II conjugation in vivo. Incubation of [14C]bropirimine with human liver microsomes resulted in the formation of a single product peak (M1) using high-performance liquid chromatography with radiochemical detection and was tentatively ass...

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Published in:	Xenobiotica Vol. 33; no. 10; pp. 999 - 1011
Main Authors:	Wynalda, M. A., Wynalda, K. M., Amore, B. M., Fagerness, P. E., Wienkers, L. C.
Format:	Journal Article
Language:	English
Published:	London Informa UK Ltd 01-10-2003 Taylor & Francis
Subjects:	Antineoplastic agents Antineoplastic Agents - pharmacology Biological and medical sciences bropirimine Chemotherapy Chromatography, High Pressure Liquid Chromatography, Liquid Cytosine - analogs & derivatives Cytosine - metabolism Enzyme Inhibitors - pharmacology Glucuronidase - metabolism glucuronidation Glucuronosyltransferase - antagonists & inhibitors Glucuronosyltransferase - metabolism Humans Kidney - metabolism Kinetics Magnetic Resonance Spectroscopy Mass Spectrometry Medical sciences Microsomes - metabolism Microsomes, Liver - drug effects Microsomes, Liver - enzymology Microsomes, Liver - metabolism Models, Chemical Pharmacology. Drug treatments Recombinant Proteins - metabolism Spectrometry, Mass, Electrospray Ionization Time Factors Antineoplastic agent Human Liver Bropirimine Glucuronic acid conjugation Metabolism In vitro
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Summary:	1. The antitumour agent bropirimine undergoes significant Phase II conjugation in vivo. Incubation of [14C]bropirimine with human liver microsomes resulted in the formation of a single product peak (M1) using high-performance liquid chromatography with radiochemical detection and was tentatively assigned as bropirimine glucuronide based on sensitivity to -glucuronidase and by obtaining the expected mass of 442 444 amu with liquid chromatography mass spectrometry. Following metabolite isolation, the structure of M1 was established as bropirimine O-glucuronide by 1H-nuclear magnetic spectroscopy. 2. Studies aimed at identifying the human liver UDP-glucuronosyltransferase (UGT) enzyme(s) involved in the glucuronidation of bropirimine were carried out using recombinant human UGTs and it was determined that glucuronidation of bropirimine was catalysed by UGT1A1, UGT1A3 and UGT1A9. Bropirimine O-glucuronidation followed Michaelis-Menten kinetics and the Km and Vmax (mean ± SD; n = 3) were 1217 ± 205 M and 667 ± 188 pmol min−1 mg−1, respectively. 3. The activity of bropirimine O-glucuronidation by human liver microsomes was inhibited by bilirubin (40%) and with mefenamic acid (80%). Although buprenorphine extensively inhibited the activity of bropirimine O-glucuronidation by UGT1A3, the inhibition profile did not parallel that observed in HLMs. 4. The results demonstrate that UGT1A9 and to a lesser extent UGT1A1 are responsible for the majority of bropirimine O-glucuronidation in man.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0049-8254 1366-5928
DOI:	10.1080/00498250310001602757