Mitoxantrone metabolism in the isolated perfused rat liver

Ehninger, Gerhard; Proksch, Barbara; Hartmann, F; Hv, Gärtner; Wilms, K.

doi:10.1007/bf00255910

Cited by 19 publications

(13 citation statements)

References 3 publications

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“…These results are in close agreement with those previously reported. The observation in man that 28% of the dose is excreted in the feces (8) within five days as well as the high rate of biliary excretion in the rat (13,22), supports the concept that bile may be the major route for the elimination of mitoxantrone. Future studies should address the biliary elimination of mitoxantrone in patients with normal and impaired liver function and assess the metabolic capabilities under these conditions as well as the amount of mitoxantrone metabolites excreted in the bile.…”

Section: Discussionmentioning

confidence: 65%

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The pharmacokinetics and metabolism of mitoxantrone in man

et al. 1985

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An HPLC method using paired-ion chromatography on RP C-18 material was developed. After sample clean up on XAD columns, mitoxantrone (Novantrone; dihydroxyanthracenedione) in concentrations below 1 ng/ml in serum and 0.2 ng/ml in urine were measurable with a coefficient of variation less than 9.3% at a wavelength of 658 nm. Four metabolites were separated in urine. The major metabolite cochromatographed with the synthesized dicarboxylic acid of mitoxantrone. Within 48 hours 4.4% of the administered dose was excreted in urine as mitoxantrone, 0.5% as metabolite 1 and 0.3% as metabolite 2. The pharmacokinetic parameters are adequately described by a three-compartment model with a terminal half-life of 214.8 hours, and a volume of distribution (ss) of 3792 litres. The total body clearance was 358 ml/min and the renal clearance was 26.2 ml/min.

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Section: Discussionmentioning

confidence: 65%

“…Reported pharmacokinetic data are controversial, with the elimination half-life varying between 56 minutes and 42.6 hours (8)(9)(10)(11)(12). Our group has prcviously reportcd on the extensive metabolism in the isolated perfused rat liver (13,14) and has described metabolites in man (15).…”

Section: Introduction Methodsmentioning

confidence: 99%

The pharmacokinetics and metabolism of mitoxantrone in man

et al. 1985

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“…Thirdly, urine HPLC chromatograms revealed up to three polar metabolites, which appeared identical to those previously observed in rat bile (27). Finally, Ehninger et al (28) have shown recently, using an isolated perfused rat liver model and thin layer chromatography assay techniques, that mitoxantrone is actively metabolised with up to three more polar compounds appearing on the thin layer plates.…”

Section: Mitoxantrone Pharmacokinetics Following Intravenous Administmentioning

confidence: 99%

Pharmacology of mitoxantrone: mode of action and pharmacokinetics

et al. 1985

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Although a number of investigators have established that mitoxantrone (Novantrone| dihydroxyanthracenedionc) inhibits RNA and DNA synthesis and intercalates with DNA in vitro, its exact mechanism of action is unclear. Mitoxantrone is structurally related to a series of substituted anthraquinones and has features known to be essential for DNA intercalation; however, we have determined recently that mitoxantrone binds DNA in intact L1210 leukemia cells by a non-intercalative, electrostatic interaction and induces both protein associated and non-protein associated DNA strand scissions. The difference between mitoxantrone and doxorubicin with respect to their interactions with DNA could account for their relative lack of cross-resistance in the treatment of lymphoma and acute leukemia.Distribution and half-life data provide a pharmacological rationale for the use of mitoxantrone on an intermittent dosing schedule. Considerable evidence exists to suggest that mitoxantrone undergoes extensive metabolism, probably in the liver. Preliminary data show that abnormal liver function leads to decreased rates of total body mitoxantrone clearance, suggesting a possible need for dose reduction in patients with severe liver dysfunction. The most important route of mitoxantrone elimination appears to be fecal. Because of the relativcly low urinary excretion it is unlikely that the standard drug dose must be reduced in the presence of compromised renal function.

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“…The biliary excretion of mitoxantrone in rats has not been fully investigated. The percentage of the dose of mitoxantrone excreted in bile has been reported in one published article and two abstracts 16–18. In one study using isolated perfused rat livers, 25.8 ± 2.6% of a 0.2 mg/kg dose was excreted into bile during 4 h, with the parent drug accounting for about 5.5%.…”

Section: Introductionmentioning

confidence: 99%