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Antitumour imidazotetrazines, Part IX. The pharmacokinetics of mitozolomide in mice.
- Source :
-
British journal of cancer [Br J Cancer] 1985 Jul; Vol. 52 (1), pp. 37-41. - Publication Year :
- 1985
-
Abstract
- Mitozolomide is a novel antitumour agent showing a broad spectrum of activity against murine tumours and is currently undergoing Phase I clinical evaluation in the UK. We have conducted an animal pharmacokinetic study using male BALB/c mice as a pre-requisite to the clinical work. Mice were dosed i.p. at 5 dose levels (0.25-20 mg kg-1) and the oral and transdermal routes of administration were investigated at 20 mg kg-1. The analytical data produced a good fit to a simple open one-compartment pharmacokinetic model with an elimination half-life of the drug from plasma of between 0.68 and 0.88 h over the 0.25-20 mg kg-1 range covered. There was no evident dose dependency over this range and studies with two formulations showed mitozolomide to have good systemic availability when administered via the oral route (F values of 0.66 and 0.81). The drug was also found to be systemically available when administered topically in dimethylsulfoxide (F = 0.47). Mitozolomide shows many biochemical and biological similarities to the clinically used nitrosoureas BCNU and CCNU but our results show that it differs markedly in its kinetics from these two agents, with mitozolomide having relatively sustained plasma levels. It is hoped that this may be of therapeutic benefit if these levels are reflected in relative tumour concentrations.
- Subjects :
- Administration, Oral
Animals
Antineoplastic Agents administration & dosage
Antineoplastic Agents blood
Biological Availability
Dose-Response Relationship, Drug
Half-Life
Injections, Intradermal
Kinetics
Male
Mice
Mice, Inbred BALB C
Nitrogen Mustard Compounds administration & dosage
Nitrogen Mustard Compounds blood
Antineoplastic Agents metabolism
Nitrogen Mustard Compounds metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0007-0920
- Volume :
- 52
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- British journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 4015951
- Full Text :
- https://doi.org/10.1038/bjc.1985.145