Metabolism of methoxymorpholino‐doxorubicin in rat, dog and monkey liver microsomes: comparison with human microsomes

Beulz-Riché, Dominique; Robert, Jacques; Menard, Christophe; Ratanasavanh, Damrong

doi:10.1046/j.1472-8206.2001.dc053.x

Cited by 5 publications

(4 citation statements)

References 14 publications

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“…The rabbit is a representative animal showing cardiac responses [20], while in the dog [21] effects on central nervous system are the main response; rhesus monkey produces mixed-type responses [22]. However, despite the large number of investigations made, the results obtained in animal models are still hard to be translated to humans; therefore there is a critical need for continued translational research and animal studies to improve our understanding of the molecular mechanisms that underlie the cardiac dysfunction of antiblastic drugs.…”

Section: Introductionmentioning

confidence: 99%

Animal Models in Studies of Cardiotoxicity Side Effects from Antiblastic Drugs in Patients and Occupational Exposed Workers

Lamberti

Giovane

Garzillo

et al. 2014

BioMed Research International

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Cardiotoxicity is an important side effect of cytotoxic drugs and may be a risk factor of long-term morbidity for both patients during therapy and also for staff exposed during the phases of manipulation of antiblastic drugs. The mechanism of cardiotoxicity studied in vitro and in vivo essentially concerns the formation of free radicals leading to oxidative stress, with apoptosis of cardiac cells or immunologic reactions, but other mechanisms may play a role in antiblastic-induced cardiotoxicity. Actually, some new cytotoxic drugs like trastuzumab and cyclopentenyl cytosine show cardiotoxic effects. In this report we discuss the different mechanisms of cardiotoxicity induced by antiblastic drugs assessed using animal models.

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Section: Introductionmentioning

confidence: 99%

Animal Models in Studies of Cardiotoxicity Side Effects from Antiblastic Drugs in Patients and Occupational Exposed Workers

Lamberti

Giovane

Garzillo

et al. 2014

BioMed Research International

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“…The reduction was also observed in RLMs and HLMs but to a much smaller extent. Carbonyl reduction in liver microsomes has been reported previously (Beulz-Riche et al, 2001). It should be noted that estimation of the amounts of reduced metabolites formed in liver microsomes may be difficult because the metabolites may be subject to redox cycling.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange

Johansson¹,

Weidolf²,

Popp³

et al. 2010

Drug Metabolism and Disposition

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ABSTRACT:The neurotoxic side effects observed for the neuroleptic agent haloperidol have been associated with its pyridinium metabolite. In a previous study, a silicon analog of haloperidol (sila-haloperidol) was synthesized, which contains a silicon atom instead of the carbon atom in the 4-position of the piperidine ring. In the present study, the phase I metabolism of sila-haloperidol and haloperidol was studied in rat and human liver microsomes. The phase II metabolism was studied in rat, dog, and human hepatocytes and also in liver microsomes supplemented with UDP-glucuronic acid (UDPGA). A major metabolite of haloperidol, the pyridinium metabolite, was not formed in the microsomal incubations with silahaloperidol. For sila-haloperidol, three metabolites originating from opening of the piperidine ring were observed, a mechanism that has not been observed for haloperidol. One of the significant phase II metabolites of haloperidol was the glucuronide of the hydroxy group bound to the piperidine ring. For sila-haloperidol, the analogous metabolite was not observed in the hepatocytes or in the liver microsomal incubations containing UDPGA. If silanol (SiOH) groups are not glucuronidated, introducing silanol groups in drug molecules could provide an opportunity to enhance the hydrophilicity without allowing for direct phase II metabolism. To provide further support for the observed differences in metabolic pathways between haloperidol and sila-haloperidol, the metabolism of another pair of C/Si analogs was studied, namely, trifluperidol and sila-trifluperidol. These studies showed the same differences in metabolic pathways as between sila-haloperidol and haloperidol.Haloperidol was developed in the late 1950s and was found to be a potent neuroleptic agent (Janssen et al., 1959). Haloperidol is a dopamine (D 2 ) receptor antagonist and is still used in the treatment of schizophrenia, although it may cause severe extrapyramidal side effects, including parkinsonism and tardive dyskinesia (Levinson, 1991;Casey, 1995). The pyridinium metabolite of haloperidol has been proposed to contribute to these neurotoxic side effects because it structurally resembles 1-methyl-4-phenylpyridinium (commonly referred to as MMP ϩ ), an inducer of Parkinson disease-like symptoms (Subramanyam et al., 1991a;Dauer and Przedborski, 2003).In the search for analogs of haloperidol, a silicon analog (silahaloperidol) was synthesized, where the quaternary R 3 COH carbon atom in the piperidine ring was replaced by a silicon atom (R 3 SiOH). The synthesis and the physicochemical and pharmacological properties of sila-haloperidol have been reported previously (Tacke et al., 2004a(Tacke et al., , 2008. As a minor part of an extensive study of sila-haloperidol, including synthesis and pharmacological properties, three major phase I metabolites in human liver microsomes (HLMs) were tentatively identified. One of these metabolites was proposed to be formed via N-dealkylation and the other two by opening of the piperidine ring (Tacke et al., 2008). Th...

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“…P450-activated MMDX is highly cytotoxic and induces DNA-DNA cross-links (Lau et al, 1994), in contrast to MMDX itself, which, like doxorubicin, induces DNA strand breaks (Ross et al, 1979). Six to eight distinct metabolites are formed when MMDX is incubated with liver microsomes, depending on the species and the MMDX concentration (Beulz-Riche et al, 2001). Among these, the only characterized metabolite detected both in human patients and in animals is MMDX-ol (PNU-155051).…”

Section: Discussionmentioning

confidence: 99%

“…However, this metabolite is formed by an aldo-keto reductase without the involvement of cytochrome P450 and is less cytotoxic than MMDX (Breda et al, 2000). Several other characterized and uncharacterized MMDX metabolites are formed by human liver microsomes in a reaction that can be inhibited by CYP3A4 substrates (Beulz-Riche et al, 2001, 2002. However, the potential role of these metabolites in MMDX cytotoxicity remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Lü¹,

Waxman²

2004

Mol Pharmacol

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Methoxymorpholinyl doxorubicin (MMDX) is a novel liver cytochrome P450 (P450)-activated anticancer prodrug whose toxicity toward cultured tumor cells can be potentiated up to 100-fold by incubation with liver microsomes and NADPH. In the present study, a panel of human liver microsomes activated MMDX with potentiation ratios directly correlated to the CYP3A-dependent testosterone 6␤-hydroxylase activity of each liver sample. Microsome-activated MMDX exhibited nanomolar IC 50 values in growth-inhibition assays of human tumor cell lines representing multiple tissues of origin: lung (A549 cells), brain (U251 cells), colon (LS180 cells), and breast (MCF-7 cells). Analysis of individual cDNA-expressed CYP3A enzymes revealed that rat CYP3A1 and human CYP3A4 activated MMDX more efficiently than rat CYP3A2 and that human P450s 3A5 and 3A7 displayed little or no activity. MMDX cytotoxicity was substantially increased in Chinese hamster ovary cells after stable expression of CYP3A4 in combination with P450 reductase. CYP3A activation of MMDX abolished the parent drug's residual cross-resistance in a doxorubicin-resistant MCF-7 cell line that overexpresses P-glycoprotein. CYP3A-activated MMDX displayed a comparatively high intrinsic stability, with a t 1/2 of ϳ5.5 h at 37°C. MMDX was rapidly activated by CYP3A at low (ϳ1-5 nM) prodrug concentrations, with 100% tumor cell kill obtained after as short as a 2-h exposure to the activated metabolite. These findings demonstrate that MMDX can be activated by CYP3A metabolism to a potent, long-lived, and cell-permeable cytotoxic metabolite and suggest that this anthracycline prodrug may be used in combination with CYP3A4 in a P450 prodrug activation-based gene therapy for cancer treatment.

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Metabolism of methoxymorpholino‐doxorubicin in rat, dog and monkey liver microsomes: comparison with human microsomes

Cited by 5 publications

References 14 publications

Animal Models in Studies of Cardiotoxicity Side Effects from Antiblastic Drugs in Patients and Occupational Exposed Workers

Animal Models in Studies of Cardiotoxicity Side Effects from Antiblastic Drugs in Patients and Occupational Exposed Workers

In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

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