Pharmacokinetics of mitomycin C in non-oat cell carcinoma of the lung

Buice, Robert G.; Niell, Harvey B.; Sidhu, Paramjeet; Gurley, Bill J.

doi:10.1007/bf00401436

Cited by 15 publications

(4 citation statements)

References 12 publications

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“…The elimination from the central compartment (k12, k21, k13) for both dosage regimens shows the same characteristic profile during the first half hour as found in recent studies (4,5). Combination of MMC with Spherex lowers biological half life significantly as compared with conventional MMC administrations.…”

supporting

confidence: 56%

Pharmacokinetics of mitomycin C in patients after bolus injection and chemobolisation of the hepatic artery with Spherex starch particles

Czejka

Jäger

Schüller

1992

Eur. J. Drug Metab. Pharmacokinet.

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The pharmacokinetics of mitomycin C after chemobolisation of the common hepatic artery by micronized Spherex starch particles (mean particle size 30 microns) were investigated in 5 cancer patients. Bolus injection and simultaneous occlusion of the artery lead to a significantly lower systemic circulation of mitomycin C in the blood vessel system than after bolus injection without chemobolisation. The plasma concentration-time curves showed lower values in the alpha-phase in the presence of Spherex (co = 743 ng/ml) than without starch particles (co = 987 ng/ml). Accordingly, the AUC values were significantly lower too (AUC = 28.6 micrograms/ml.h with Spherex and 39.7 micrograms/ml.h without Spherex), thus leading to a lower systemic bioavailability of the drug and a higher local bioavailability in the tumor region. Elimination of mitomycin from the central compartment was similar for both administrations (t1/2 = 27 min with Spherex and 28 min without Spherex) and showed the characteristic profile of the substance. The clinical picture showed a milder toxicity with a certain loss of side effects. These results indicate a significant and desirable change in the pharmacokinetics of mitomycin C during the distribution phase into the tissue of patients.

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supporting

confidence: 56%

Pharmacokinetics of mitomycin C in patients after bolus injection and chemobolisation of the hepatic artery with Spherex starch particles

Czejka

Jäger

Schüller

1992

Eur. J. Drug Metab. Pharmacokinet.

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“…The in vitro studies in mouse, rat, and human recombinant enzyme preparations show that the mouse and human enzymes show similar kinetics of inactivation by MMC. In vivo studies with MMC show that treatment at doses (10 and 20 mg/kg) that correspond to appreciably higher plasma and tissue levels than those seen in humans presently undergoing MMC therapy (van Hazel et al, 1983;Buice et al, 1984) results in significant inhibition in lung and kidney tissue but not in other tissues measured. Whether inhibition of NQO1 occurs following exposure of patients with therapeutic doses of MMC remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of NAD(P)H:Quinone Oxidoreductase I (NQO1) Inhibition by Mitomycin C in Vitro and in Vivo

Gustafson¹,

Siegel²,

Rastatter³

et al. 2003

J Pharmacol Exp Ther

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The bioreductive activation of the antitumor quinone mitomycin C (MMC) by NAD(P)H: quinone oxidoreductase 1 (NQO1) is complicated by the ability of MMC to also act as a mechanismbased inhibitor of NQO1 in a pH dependent manner. Inhibition of NQO1 by MMC has been studied in purified enzyme preparations and in cultured cells but has not determined in vivo. In the studies presented here, NQO1 activity was measured in mouse tissues following treatment with MMC or the potent mechanism-based human NQO1 inhibitor 5-methoxy-1,2-dimethyl-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936). NQO1 activity was significantly decreased at 1, 2, and 4 h following MMC (10 or 20 mg/kg) treatment in kidney and lung but was unchanged in brain, heart, liver, and bladder. ES936 (1 mg/kg) treatment led to a significant and much more potent inhibition of NQO1 in all murine tissues analyzed except for bladder. To extrapolate these in vivo results from mice to humans, the species-specific kinetics of NQO1 inactivation by MMC was determined in vitro using mouse, rat, and human recombinant NQO1 proteins. Results showed the inactivation kinetics of mouse and human proteins by MMC were similar. Treatment of human and murine endothelial cells with MMC or ES936 showed similar inhibition of NQO1 activity. The aforementioned results clearly demonstrate that MMC can serve as a substrate for NQO1 in vivo; however, the metabolism resulting in enzyme inactivation is possibly tissue-specific. Furthermore, the kinetic similarities for inactivation between murine and human forms of NQO1 show these results are apropos to clinical use of MMC.Although it is clear that NAD(P)H:quinone oxidoreductase 1 (NQO1; EC 1.6.99.2) is capable of reducing the antineoplastic antibiotic mitomycin C (MMC) in vitro (Siegel et al., 1990b, the role of this enzyme in determining the toxicity of MMC remains controversial. A correlative relationship has been shown between NQO1 activity levels and sensitivity to MMC in the NCI tumor cell line panel (Fitzsimmons et al., 1996). Nevertheless, transfection and expression of NQO1 in cell lines has produced varied results (Powis et al., 1995;Belcourt et al., 1996;Gustafson et al., 1996;Winski et al., 1998), as have xenograft studies (Malkinson et al., 1992;Nishiyama et al., 1995;Phillips et al., 2001). The lack of an apparent relationship between NQO1 levels and MMC toxicity is not surprising for a number of reasons. MMC can be metabolically activated by multiple enzyme systems including NADPH:cytochrome P450 reductase (Keyes et al., 1984;Pan et al., 1984), cytochrome b 5 reductase (Hodnick and Sartorelli, 1993), xanthine oxidase/dehydrogenase (Pan et al., 1984;Gustafson and Pritsos, 1992), and probably others not yet identified. MMC bioactivation by NQO1 is pH dependent in vitro (Siegel et al., 1990b), and this pH dependence seems to be due to inactivation of NQO1 by MMC at more neutral pH. Furthermore, evidence suggests that the relationship between NQO1 levels and the toxicity of bioreductive substrates is best described by ...

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“…The pharmacokinetic behavior of MMC administered through a peripheral vein has been studied by several authors17-21. Some [18][19][20][21][22] have also investigated the pharmacokinetics of MMC administered in combination with other antineoplastic agents. van Hazel et al 2 reported that other antineoplasti'c agents did not apparently affect the pharmacokinetic course of MMC, while Verweij et al 9 found that total body clearance of MMC was obviously increased, whereas the area under the curve (AUC) remarkably decreased when MMC was used in combination with other antitumor agents.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Mitomycin C Following Hepatic Arterial Chemoembolization With Gelfoam

Ding

Andersson

et al. 1991

HPB Surgery

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Twelve mongrel dogs were randomly allocated into two groups using matched paired-design. Catheters were inserted into the hepatic artery, hepatic vein and the femoral vein, respectively. In the first group, gelfoam supplemented with mitomycin C (MMC) was injected into the hepatic artery, whereas the second group received a hepatic arterial injection of MMC solution alone. Simultaneous blood sampling from the hepatic and femoral veins at regular intervals was performed. MMC concentrations in plasma was determined using high performance liquid chromatography (HPLC) and the pharmacokinetics of MMC were determined. MMC concentrations in hepatic and femoral veins did not differ and no significant difference in pharmacokinetics was found when comparing MMC administration into the hepatic artery with or without gelfoam supplementation. Thus, our results revealed that gelfoam could not delay the clearance of MMC from the liver.

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Pharmacokinetics of mitomycin C in non-oat cell carcinoma of the lung

Cited by 15 publications

References 12 publications

Pharmacokinetics of mitomycin C in patients after bolus injection and chemobolisation of the hepatic artery with Spherex starch particles

Pharmacokinetics of mitomycin C in patients after bolus injection and chemobolisation of the hepatic artery with Spherex starch particles

Kinetics of NAD(P)H:Quinone Oxidoreductase I (NQO1) Inhibition by Mitomycin C in Vitro and in Vivo

Pharmacokinetics of Mitomycin C Following Hepatic Arterial Chemoembolization With Gelfoam

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