Metabolism of the anticancer drug flavopiridol, a new inhibitor of cyclin dependent kinases, in rat liver.
Flavopiridol (FLAP) is a promising novel chemotherapeutic agent currently undergoing clinical phase I trials. To examine hepatic metabolism and biliary disposition of FLAP we applied the isolated perfused rat liver system. Besides FLAP two metabolites were detected by high performance liquid chromatography in bile and perfusate. Twenty-five min after FLAP (30 microM) addition to the perfusion medium, biliary secretion of metabolite 1 and 2 reached a maximum of 1.04 +/- 0.52 and 11.34 +/- 4.72 nmol/g.liver.min, respectively. Biliary excretion of parent FLAP, however, continuously increased for 60 min up to 406 +/- 134 pmol/g liver.min. In the perfusate, metabolite 1 was below detection limit and release of metabolite 2 was low (2.8 +/- 0.7 pmol/g liver.min after 60 min). Enzymatic hydrolysis with beta-glucuronidase, mass spectroscopy and electron absorption spectroscopy revealed that both metabolites are monoglucuronides with the glucuronide in position 5 and 7 of the flavonoid core, respectively. The amount of FLAP, metabolite 1 and metabolite 2 excreted into bile during the 60 min of perfusion was 1.94 +/- 0.91, 5.15 +/- 1.95 and 57.29 +/- 23.60% of FLAP cleared from the perfusate during 60 min, respectively. In contrast to the structurally similar flavonoids genistein and daidzein, no inhibition of UDP-glucuronyltransferase with methylumbelliferone as a substrate was observed indicating that different UDP-glucuronyltransferase isoforms are involved in FLAP metabolism. In conclusion, we find that glucuronidation is the major mechanism of hepatic FLAP biotransformation. Metabolites are mainly excreted into bile but also released into systemic circulation. The pharmacological and toxicological effects of these metabolites remain to be elucidated.
Jäger
W
W
Institute of Pharmaceutical Chemistry, University of Vienna, Austria. wjaeger@speedy.pch.univie.ac.at
Zembsch
B
B
Wolschann
P
P
Pittenauer
E
E
Senderowicz
A M
AM
Sausville
E A
EA
Sedlacek
H H
HH
Graf
J
J
Thalhammer
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005419:Flavonoids / Q000378:metabolism* / Q000494:pharmacology; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D006868:Hydrolysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005965:Glucuronates; D010880:Piperidines; C077990:alvocidib; D014453:Glucuronosyltransferase; D018844:Cyclin-Dependent Kinases