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.
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.
Shukla
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A
Mental Health Research Institute, University of Michigan, Ann Arbor 48104.
Radin
N S
NS
D000818:Animals; D001834:Body Water / Q000378:metabolism; D002927:Cimetidine / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004357:Drug Synergism; D005963:Glucosylceramides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D009025:Morpholines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D010105:Oxygenases / Q000037:antagonists & inhibitors*; D010882:Piperonyl Butoxide / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D005963:Glucosylceramides; D009025:Morpholines; D014316:Tritium; C033110:RV 538; D002927:Cimetidine; D010105:Oxygenases; D010882:Piperonyl Butoxide