Penclomedine [3,5-dichloro-4,6-dimethoxy-2-(trichloromethyl)
pyridine], an
antitumor agent, is currently in Phase I clinical trials and is believed to be a
prodrug. In these studies, cerebellar effects have been dose limiting. Previous studies identified
4-demethylpenclomedine (4-DM-PEN) as the major plasma metabolite in rodents and humans.
4-DM-PEN was demonstrated to be an antitumor-active metabolite of
penclomedine in vivo when evaluated against the
penclomedine-sensitive MX-1 human
breast tumor xenograft implanted either s.c. or intracerebrally and is believed to be on the metabolic activation pathway of
penclomedine. Because earlier studies revealed an absence of neurotoxic cerebellar effects for
4-DM-PEN in contrast to
penclomedine in a rat model, this metabolite may be a candidate for an alternative to
penclomedine in the clinic for treatment of
breast cancer or
brain tumors, if the cerebellar effects of
penclomedine preclude its further clinical development. Because neither
penclomedine nor
4-DM-PEN were very active in vitro, the metabolism of
penclomedine was also investigated using rat liver microsomes in an attempt to identify the ultimate active form of the
drug. Metabolites and putative metabolites were prepared by chemical synthesis for antitumor evaluation in vitro and in vivo. A reductive metabolite, alpha,alpha-didechloro-PEN, was observed to be much more cytotoxic than
penclomedine or
4-DM-PEN in vitro, but evaluation of this and the other metabolites and putative metabolites in vivo against the MX-1
tumor failed to identify any active metabolite among the structures evaluated other than
4-DM-PEN. The limited activity of
4-DM-PEN in vitro indicates that it, like
penclomedine, is also a
prodrug, demonstrating a need for additional studies on the metabolic activation of
penclomedine to identify the ultimate active form of the
drug.