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Vol. 29, Issue 4, 407-414, April 2001

In Vitro Glucuronidation of the Cyclin-Dependent Kinase Inhibitor Flavopiridol by Rat and Human Liver Microsomes: Involvement of UDP-Glucuronosyltransferases 1A1 and 1A9

Birgit Hagenauer, Alexandra Salamon, Therese Thalhammer, Olaf Kunert, Ernst Haslinger, Paul Klingler, Adrian M. Senderowicz, Edward A. Sausville, and Walter Jäger

Institute of Pharmaceutical Chemistry (B.H., A.S., W.J.) and Department of Pathophysiology, (T.T.), University of Vienna, Vienna, Austria; Institute of Pharmaceutical Chemistry, University of Graz, Graz, Austria (O.K., E.H.); Department of Surgery, University-Hospital of Innsbruck, Innsbruck, Austria (P.K.); and National Institutes of Health (A.M.S.) and National Cancer Institute (E.A.S.), Bethesda, Maryland

The metabolism of flavopiridol (FLAP), a novel anticancer drug currently undergoing clinical development, was investigated in rat and human liver microsomes. In the presence of uridine 5'-diphosphoglucuronic acid, two biotransformation products (M1 and M2) could be detected. Formation of metabolite M1 and M2 in terms of enzymatic efficacy (Vmax/KM) was about 50- and 5-fold higher in rat (1.58 ± 2.23 and 7.22 ± 1.17 µl/min/mg) as compared with human liver microsomes (0.032 ± 0.016 and 1.52 ± 0.93 µl/min/mg), indicating species-related differences in FLAP glucuronidation. Incubation in the presence of human recombinant UDP-glucuronosyltransferases (UGTs) demonstrated that M1 is almost exclusively catalyzed by UGT1A1, whereas M2 is formed by UGT1A9 and only to a minor extent by UGT1A1 and UGT1A10. Chemical inhibition experiments further prove the involvement of UGT1A1 and UGT1A9 in the formation of M1 and M2, as the UGT1A1 substrate bilirubin preferably inhibited M1 over M2 (Ki: 36 and 258 µM, respectively), whereas the UGT1A9 substrate propofol showed a more pronounced decrease in M2 but not in M1 formation (Ki: 47 and 142 µM, respectively). Both conjugates were purified from rat liver microsomes and analyzed by mass spectrometry, NMR, and UV experiments. On the basis of these results, M1 was identified as 5-O-beta -glucopyranuronosyl-flavopiridol and M2 as 7-O-beta -glucopyranuronosyl-flavopiridol. In conclusion, our results elucidate the enzymatic pathways of FLAP in rat and human liver, which must be considered during cancer therapy of patients.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics.