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Pharmacokinetics and metabolism of the nitrogen mustard bioreductive drug 5-( N , N -bis(2-chloroethyl)amino)-2,4-dinitrobenzamide (SN 23862) and the corresponding aziridine (CB 1954) in KHT tumour-bearing mice

Pharmacokinetics and metabolism of the nitrogen mustard bioreductive drug 5-( N , N... Purpose : To characterise the pharmacokinetics and metabolism in mice of 5-( N , N -bis(2-chloroethyl)amino)-2,4-dinitrobenzamide (SN 23862), the lead compound of a new class of bioreductive drugs in which a nitrogen mustard is activated by nitroreduction. Comparison is made with the corresponding aziridine derivative CB 1954. Methods : Male C 3 H/HeN mice, bearing s.c. KHT tumours, received 3 H-labelled SN 23862 or CB 1954 i.v. at 200 μmol/kg. Plasma, urine and tumour samples were assayed for total radioactivity, and for parent compounds by HPLC. Metabolites were identified by 1 H-NMR and mass spectrometry. Cytotoxicity of compounds against Chinese hamster AA8 cells was determined by growth inhibition assay. Results : The plasma pharmacokinetics of SN 23862 and CB 1954 were similar, with half-lives of 1.1 and 1.2 h, respectively. SN 23862 provided tumour/plasma ratios and absolute tumour AUC values almost two times higher than CB 1954. Despite this, SN 23862 was more extensively metabolised than CB 1954, the major route being sequential oxidative dechloroethylation of the nitrogen mustard moiety to the relatively non-toxic half mustard and 5-amine. The inferred chloroacetaldehyde co-product was 260 times more potent than SN 23862. A tetrahydroquinoxaline metabolite resulting from reduction of the 4-nitro group followed by intramolecular alkylation was weakly cytotoxic, while the more cytotoxic 2-amino derivative of SN 23862 was detected in trace amounts. CB 1954 was metabolised by analogous pathways, but the 4- and 2-amine nitroreduction products were the major metabolites while oxidative dealkylation was minor. Conclusion : The lesser propensity for SN 23862 to undergo nitroreduction in the host, relative to CB 1954, argues that dinitrobenzamide mustards may be preferable to the corresponding aziridines as bioreductive prodrugs for cancer treatment. However, the toxicological significance of oxidative metabolism of the bis(2-chloroethyl)amine moiety needs to be addressed. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Chemotherapy and Pharmacology Springer Journals

Pharmacokinetics and metabolism of the nitrogen mustard bioreductive drug 5-( N , N -bis(2-chloroethyl)amino)-2,4-dinitrobenzamide (SN 23862) and the corresponding aziridine (CB 1954) in KHT tumour-bearing mice

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Publisher
Springer Journals
Copyright
Copyright © 2000 by Springer-Verlag Berlin Heidelberg
Subject
Legacy
ISSN
0344-5704
eISSN
1432-0843
DOI
10.1007/s002800000165
Publisher site
See Article on Publisher Site

Abstract

Purpose : To characterise the pharmacokinetics and metabolism in mice of 5-( N , N -bis(2-chloroethyl)amino)-2,4-dinitrobenzamide (SN 23862), the lead compound of a new class of bioreductive drugs in which a nitrogen mustard is activated by nitroreduction. Comparison is made with the corresponding aziridine derivative CB 1954. Methods : Male C 3 H/HeN mice, bearing s.c. KHT tumours, received 3 H-labelled SN 23862 or CB 1954 i.v. at 200 μmol/kg. Plasma, urine and tumour samples were assayed for total radioactivity, and for parent compounds by HPLC. Metabolites were identified by 1 H-NMR and mass spectrometry. Cytotoxicity of compounds against Chinese hamster AA8 cells was determined by growth inhibition assay. Results : The plasma pharmacokinetics of SN 23862 and CB 1954 were similar, with half-lives of 1.1 and 1.2 h, respectively. SN 23862 provided tumour/plasma ratios and absolute tumour AUC values almost two times higher than CB 1954. Despite this, SN 23862 was more extensively metabolised than CB 1954, the major route being sequential oxidative dechloroethylation of the nitrogen mustard moiety to the relatively non-toxic half mustard and 5-amine. The inferred chloroacetaldehyde co-product was 260 times more potent than SN 23862. A tetrahydroquinoxaline metabolite resulting from reduction of the 4-nitro group followed by intramolecular alkylation was weakly cytotoxic, while the more cytotoxic 2-amino derivative of SN 23862 was detected in trace amounts. CB 1954 was metabolised by analogous pathways, but the 4- and 2-amine nitroreduction products were the major metabolites while oxidative dealkylation was minor. Conclusion : The lesser propensity for SN 23862 to undergo nitroreduction in the host, relative to CB 1954, argues that dinitrobenzamide mustards may be preferable to the corresponding aziridines as bioreductive prodrugs for cancer treatment. However, the toxicological significance of oxidative metabolism of the bis(2-chloroethyl)amine moiety needs to be addressed.

Journal

Cancer Chemotherapy and Pharmacology – Springer Journals

Published: Nov 1, 2000

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