Journal of Lipid Research, Vol 32, 713-722, Copyright © 1991 by Lipid Research, Inc.
Metabolism of D-[3H]threo-1-phenyl-2-decanoylamino-3-morpholino-1- propanol, an inhibitor of glucosylceramide synthesis, and the synergistic action of an inhibitor of microsomal monooxygenase
A Shukla and NS Radin
Mental Health Research Institute, University of Michigan, Ann Arbor 48104.
D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) is an
effective inhibitor of the glucosyltransferase that makes glucosylceramide.
Virtually all of the hundreds of naturally occurring glycolipids are formed
from this primary glycolipid, so the inhibitor acts to lower their
concentrations by the process of attrition (hydrolytic catabolism). Trials
with mice carrying ascites carcinoma cells showed that PDMP could produce a
permanent cure in some of the animals and marked prolongation of life in
the others (Inokuchi, J., I. Mason, and N.S. Radin. 1987. Cancer Lett. 38:
23-30). In order to maximize the effect, we studied the metabolism of PDMP
by labeling it with [3H] on carbon one, using a labeling method that
discriminated against the unwanted erythro-isomer. The active enantiomer of
the inhibitor (D-) was isolated by chromatography of the camphanate esters,
followed by methanolytic cleavage. Examination of the fate of the labeled
drug after a single injection showed that it was very rapidly converted to
several polar products that were rapidly excreted. The drug penetrated all
of the organs readily and a small portion was oxidized at the C-1 position
to yield 3H2O. From these findings it appeared likely that the amine is
attacked by a mixed function oxidase based on cytochrome P450. This
conclusion was confirmed by showing that the tissue levels of PDMP could be
greatly elevated, for a much longer time, when the mice were pretreated
with piperonyl butoxide or cimetidine. The amount of conversion to polar
metabolites was substantially reduced and tissue levels of PDMP were
maintained much longer. Analysis of mice injected with one or both drugs
showed that piperonyl butoxide augmented the effects of PDMP on ceramide,
glucosylceramide, and dihexosylceramide levels, as well as on the activity
of glucosylceramide synthase. It is suggested that piperonyl butoxide be
used as an adjuvant for the many useful drugs that are inactivated by the
P450 system.
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