Biliary excretion of flavopiridol and its glucuronides in the isolated perfused rat liver: role of multidrug resistance protein 2 (Mrp2)

Jäger, Walter; Gehring, Eva−Maria; Hagenauer, Birgit; Aust, Sylvia; Senderowicz, Adrian M.; Thalhammer, Therese

doi:10.1016/s0024-3205(03)00699-4

Cited by 45 publications

(27 citation statements)

References 19 publications

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“…The mean liver weights of the TR Ϫ rats were significantly greater than those of the Wistar rats, but there was no difference in microsomal protein concentrations. The significant difference in rat and liver weights identified in this study is consistent with those differences seen by Jager et al (2003).…”

Section: Resultssupporting

confidence: 90%

Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR^- Rat Liver Microsomes

Westley

Morris²,

Evans³

et al. 2007

Drug Metab Dispos

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Section: Resultssupporting

confidence: 90%

Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR^- Rat Liver Microsomes

Westley

Morris²,

Evans³

et al. 2007

Drug Metab Dispos

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“…Drug-drug interactions would not be expected with loperamide and flavopiridol, which is eliminated primarily by glucuronidation and biliary excretion of both parent and glucuronide metabolites. [38][39][40][41] Additionally, our flavo-G data do not support the latter hypothesis, as we saw no indication of upregulation of UGT activity between days 1 and 3 (data not shown). Measureable increases in flavopiridol trough levels were observed in this study, although AUCs did not significantly change between days 1 and 3.…”

contrasting

confidence: 55%

Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias

Blum¹,

Phelps²,

Klisovic³

et al. 2010

Haematologica

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BackgroundA pharmacokinetically derived schedule of flavopiridol administered as a 30 min intravenous bolus followed by 4-hour continuous intravenous infusion (IVB/CIVI) is active in fludarabinerefractory chronic lymphocytic leukemia, but no studies examining the feasibility and maximum tolerated dose of this schedule have been reported in acute leukemia. Design and MethodsWe conducted a phase I dose escalation trial of single-agent flavopiridol in adults with relapsed/refractory acute leukemias, utilizing a modification of the intravenous bolus/continuous intravenous infusion approach, intensifying treatment for administration on days 1, 2, and 3 of 21-day cycles. ResultsTwenty-four adults with relapsed/refractory acute myeloid leukemia (n=19) or acute lymphoblastic leukemia (n=5) were enrolled. The median age was 62 years (range, 23-78). The maximum tolerated dose of flavopiridol was 40mg/m 2 intravenous bolus plus 60mg/m 2 continuous intravenous infusion (40/60). The dose limiting toxicity was secretory diarrhea. Lifethreatening hyperacute tumor lysis syndrome requiring hemodialysis on day 1 was observed in one patient. Pharmacokinetics were dose-dependent with increased clearance observed at the two highest dose levels. Diarrhea occurrence and severity significantly correlated with flavopiridol concentrations at the end of the 4-hour infusion, volume of distribution, and elimination half-life. Modest anti-leukemic activity was observed, with most patients experiencing dramatic but transient reduction/clearance of circulating blasts lasting for 10-14 days. One refractory acute myeloid leukemia patient had short-lived complete remission with incomplete count recovery. ConclusionsFlavopiridol as a single agent given by intravenous bolus/continuous intravenous infusion causes marked, immediate cytoreduction in relapsed/refractory acute leukemias, but objective clinical responses were uncommon. With this schedule, the dose is limited by secretory diarrhea (ClinicalTrials.gov Identifier: NCT00101231).

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“…Groningen Yellow/Transport-deficient Wistar rats (Jansen et al, 1987;Paulusma et al, 1996) and Eisai hyperbilirubinemic Sprague-Dawley rats (EHBR) (Ito et al, 1997) are used most commonly as preclinical models of cholestatic patients with Dubin-Johnson syndrome. To date, many studies have been performed to characterize drug disposition in Abcc2-deficient rats (Jager et al, 2003;Hanawa et al, 2004;Takayanagi et al, 2005). In addition, it has been reported that in Abcc2-deficient rats, expression of the basolateral membrane transporter Abcc3 is up-regulated, which results in increased excretion of organic anions across the sinusoidal membrane (Xiong et al, 2002;Kuroda et al, 2004); ABCC3 expression is also up-regulated in patients with Dubin-Johnson syndrome .…”

mentioning

confidence: 99%

ALTERED HEPATOBILIARY DISPOSITION OF 5 (AND 6)-CARBOXY-2′,7′-DICHLOROFLUORESCEIN INAbcg2(Bcrp1) ANDAbcc2(Mrp2) KNOCKOUT MICE

Nezasa

Tian²,

Zamek‐Gliszczynski³

et al. 2006

Drug Metab Dispos

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ABSTRACT:This study characterized the hepatobiliary disposition of 5 (and 6)-carboxy-2,7-dichlorofluorescein (CDF), a model Abcc2/Mrp2 (canalicular) and Abcc3/Mrp3 (basolateral) substrate, in perfused livers from male C57BL/6 wild-type, Abcg2؊/؊, and Abcc2؊/؊ mice. After single-pass liver perfusion with 1 M CDF diacetate for 30 min and an additional 30-min perfusion with CDF-free buffer, cumulative biliary excretion of CDF in Abcg2؊/؊ mice was significantly higher than in wild-type mice (65 ؎ 6 and 47 ؎ 15% of dose, respectively, p < 0.05), whereas CDF recovery in bile of Abcc2؊/؊ mice was negligible. Cumulative recovery of CDF in perfusate was significantly higher in Abcc2؊/؊ (90 ؎ 8% of dose) relative to wild-type (

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Biliary excretion of flavopiridol and its glucuronides in the isolated perfused rat liver: role of multidrug resistance protein 2 (Mrp2)

Cited by 45 publications

References 19 publications

Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR^- Rat Liver Microsomes

Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR^- Rat Liver Microsomes

Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias

ALTERED HEPATOBILIARY DISPOSITION OF 5 (AND 6)-CARBOXY-2′,7′-DICHLOROFLUORESCEIN INAbcg2(Bcrp1) ANDAbcc2(Mrp2) KNOCKOUT MICE

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Biliary excretion of flavopiridol and its glucuronides in the isolated perfused rat liver: role of multidrug resistance protein 2 (Mrp2)

Cited by 45 publications

References 19 publications

Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR- Rat Liver Microsomes

Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR- Rat Liver Microsomes

Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias

ALTERED HEPATOBILIARY DISPOSITION OF 5 (AND 6)-CARBOXY-2′,7′-DICHLOROFLUORESCEIN INAbcg2(Bcrp1) ANDAbcc2(Mrp2) KNOCKOUT MICE

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Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR^- Rat Liver Microsomes

Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR^- Rat Liver Microsomes