Metabolism of the anticancer drug flavopiridol, a new inhibitor of cyclin dependent kinases, in rat liver

doi:10.1016/S0024-3205(98)00152-0

Life Sciences

Volume 62, Issue 20, 10 April 1998, Pages 1861-1873

https://doi.org/10.1016/S0024-3205(98)00152-0 Get rights and content

Abstract

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 μM) addition to the perfusion medium, biliary secretion of metabolite l 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 β-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.

References (26)

M.D. Losiewicz et al.
Biochem. Biophys. Res. Comm.
(1994)
P.J. Worland et al.
Biochem. Pharmacol.
(1993)
R. Graeser et al.
Mol. Biochem. Parasitol.
(1996)
W. Jäger et al.
Hepatology
(1997)
T. Thalhammer et al.
Europ. J. Pharmacol.
(1994)
G.J. Mulder
Trends Pharmacol. Sci.
(1992)
H.H. Sedlacek et al.
Int. J. Oncol.
(1996)
L. Meijer et al.
Europ. J. Biochem.
(1997)
G. Kaur et al.
J. Natl. Cancer Inst.
(1992)
W.F.J.R. De-Azevedo et al.

B.A. Carlson et al.

Cancer Res.

(1996)

M. Drees et al.

Clin. Cancer Res.

(1997)

K.C. Bible et al.

Cancer Res.

(1996)

Cited by (66)

An ethnopharmacological review on the therapeutical properties of flavonoids and their mechanisms of actions: A comprehensive review based on up to date knowledge
2022, Toxicology Reports
Flavonoids -a class of low molecular weight secondary metabolites- are ubiquitous and cornucopia throughout the plant kingdom. Structurally, the main structure consists of C6-C3-C6 rings with different substitution patterns so that many sub-classes are obtained, for example: flavonols, flavonolignans, flavonoid glycosides, flavans, anthocyanidins, aurones, anthocyanidins, flavones, neoflavonoids, chalcones, isoflavones, flavones and flavanones. Flavonoids are evaluated to have drug like nature since they possess different therapeutic activities, and can act as cardioprotective, antiviral, antidiabetic, anti-inflammatory, antibacterial, anticancer, and also work against Alzheimer's disease and others. However, information on the relationship between their structure and biological activity is scarce. Therefore, the present review tries to summarize all the therapeutic activities of flavonoids, their mechanisms of action and the structure activity relationship.
First-pass metabolism via UDP-glucuronosyltransferase: A barrier to oral bioavailability of phenolics
2011, Journal of Pharmaceutical Sciences
Citation Excerpt :
Flavopiridol (36, Fig. 8) is a cyclin-dependent kinase inhibitor for the treatment of chronic lymphocytic leukemia.170 Glucuronidation is the major mechanism for hepatic clearance of flavopiridol.171,172 Clinical toxicity (e.g., diarrhea) accompanied with this drug appeared to be inversely correlated with the magnitude of its glucuronidation.172
Glucuronidation mediated by UDP-glucuronosyltransferases (UGTs) is a significant metabolic pathway that facilitates efficient elimination of numerous endobiotics and xenobiotics, including phenolics. UGT genetic deficiency and polymorphisms or inhibition of glucuronidation by concomitant use of drugs are associated with inherited physiological disorders or drug-induced toxicities. Moreover, extensive glucuronidation can be a barrier to oral bioavailability as the first-pass glucuronidation (or premature clearance by UGTs) of orally administered agents usually results in the poor oral bioavailability and lack of efficacies. This review focused on the first-pass glucuronidation of phenolics including natural polyphenols and pharmaceuticals. The complexity of UGT-mediated metabolism of phenolics is highlighted with species-, gender-, organ- and isoform-dependent specificity, as well as functional compensation between UGT1A and 2B subfamily. In addition, recent advances are discussed with respect to the mechanisms of enzymatic actions, including the important properties such as binding pocket size and phosphorylation requirements. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3655–3681, 2011
ATPase inhibitors of heat-shock protein 90, second season
2010, Drug Discovery Today
In the past four years, the ATP-dependent heat-shock protein 90 has remained the focus of much interest. Phase I and phase II anticancer clinical trials with first-generation inhibitors, although sometimes disappointing, have yet to report a forbidding side-effect inherent to the inhibition of this chaperone, which has a very complex and widespread role in cell biochemistry. Research in the field has started to unravel an elaborate regulation picture leading to the proper folding of many proteins. On the medicinal chemistry side, a second wave of inhibitors has been reported. This review attempts to describe all the ATPase inhibitors of HSP90 reported since our last survey.
Absorption and enterohepatic circulation of baicalin in rats
2005, Life Sciences
Pharmacokinetics of baicalin, in form of its parent drug (BG) and conjugated metabolites (BGM), were studied following intravenous and oral administration of baicalin to intact rats. The enterohepatic circulation of BG and BGM was also assessed in a linked-rat model. Multiple plasma and urine samples were collected, and concentrations of BG and BGM were determined using a liquid chromatography/tandem mass spectrometry method. The concentration of BGM was assayed in the form of baicalein after treatment with β-glucuronidase/sulfatase. After i.v. administration, plasma concentration of BG rapidly declined with the elimination half-life (T_1 / 2) of 0.1 till 4 h post dose, followed by slight increase from 4–8 h in plasma concentrations after drug administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of BG (T_{1 / 2 TER}, 9.7 h). BG also displayed slight increase in plasma concentrations (12–24 h) after oral administration, with T_{1 / 2 TER} of 12.1 h. Based on the AUC of BG and BGM, the absolute bioavailability of baicalin was 2.2 ± 0.2% and 27.8 ± 5.6%, respectively. The exposure of baicalin to the systemic circulation was approximately 118-fold lower than that of BGM after oral administration (AUC_0−t, 4.43 versus 523.97 nmol·h/mL). The high extent of glucuronidation suggested the possible presence of enterohepatic circulation, which was confirmed in the linked-rat model since plasma concentrations of BG and BGM were observed in bile-recipient rats at 4 to 36 h. The extent of enterohepatic circulation after intravenous administration of baicalin was 4.8% and 13.3% for BG and BGM, respectively. It was determined that 18.7% and 19.3% of the administered baicalin were subjected to enterohepatic circulation for BG and BGM, respectively, after oral administration. These results confirm that BG undergoes extensive first-pass glucuronidation and that enterohepatic circulation contributes significantly to the exposure of BG and BGM in rats.
Biliary excretion of flavopiridol and its glucuronides in the isolated perfused rat liver: Role of multidrug resistance protein 2 (Mrp2)
2003, Life Sciences
Flavopiridol (FLAP) is a novel anticancer agent that is extensively glucuronidated in patients. Biliary excretion is the main elimination pathway of FLAP conjugates responsible for enterohepatic recirculation and for the main side effect diarrhea. To investigate the hepatic transport system for FLAP glucuronides, livers of Wistar and Mrp2-deficient TR⁻ rats were perfused with FLAP (30 μM) in a single pass system. Biliary excretion and efflux into perfusate during a 60 min period greatly differ in TR⁻ rats. While cumulative biliary excretion of M1 and M2 was significantly reduced to 4.3% and 5.4% efflux into perfusate was increased by 1.5 and 4.2-fold. This indicates that in control rats, M1 and M2 are almost exclusively eliminated into bile by Mrp2. Cumulative FLAP secretion into bile and perfusate, however, was non-significantly reduced by 36.7% and 43.2% in the mutant rat strain, suggesting that besides Mrp2, other transporters might also be involved in FLAP elimination. FLAP stimulates bile flow up to 24% in control rats, but secretion is nearly absent in TR⁻ rats further supporting an efficient transport of FLAP glucuronides by Mrp2. FLAP (30 μM) also reversibly inhibited the Mrp2-mediated biliary elimination of bilirubin and bromsulphthalein in Wistar rats by 54% and 51%, respectively, indicating a competition with the elimination of Mrp2-specific substrates. In summary, we found that FLAP glucuronides are substrates of Mrp2 effectively inhibiting the biliary excretion of bilirubin. This may explain the increased serum bilirubin levels observed in cancer patients during FLAP therapy.
The Pharmacological Implications of Flavopiridol: An Updated Overview
2023, Molecules

View all citing articles on Scopus

^☆: Presented in part at the 88th Annual Meeting of the American Association for Cancer Research, April 12–16, 1997, San Diego, CA, USA.

View full text

Metabolism of the anticancer drug flavopiridol, a new inhibitor of cyclin dependent kinases, in rat liver☆

Abstract

Biochem. Biophys. Res. Comm.

Biochem. Pharmacol.

Mol. Biochem. Parasitol.

Hepatology

Europ. J. Pharmacol.

Trends Pharmacol. Sci.

Int. J. Oncol.

Europ. J. Biochem.

J. Natl. Cancer Inst.

Cancer Res.

Clin. Cancer Res.

Cancer Res.