DISPOSITION OF L-3-[(DIMETHYLAMINO)-(M-DIOXAN-5-YL)METHYL]PYRIDINE IN MAN

  • 1 January 1979
    • journal article
    • research article
    • Vol. 7  (3) , 149-154
Abstract
3-[(Dimethylamino)-(m-dioxan-5-yl)methyl]pyridine hydrochloride (LY 108380) is being studied in man as a potentially useful, nonaddicting analgesic agent. The substituted dioxane is structurally different from any currently known analgesic. After i.m. administration of the 14C-labeled compound to healthy volunteers, the drug was absorbed rapidly (t1/2(abs) [absorption half-life] = 2-20 min). Pharmacokinetic analyses suggested that LY 108380 was widely distributed and extensively bound in tissues. The drug was not bound to plasma proteins in vitro or in vivo. In the blood radioactivity was distributed in both red cells and plasma; a cell/plasma radioactivity ratio of 0.5 was maintained for about 1 h. The t1/2 [half-life] for elimination of LY 108380-14C from plasma was 1.3 h; radioactivity persisted in plasma for over 100 h. At the time of peak radioactivity, the parent compound was the major constituent in plasma; quaternary N-glucuronide and N-desmethylated metabolites were also detected in plasma. Levels of radioactivity in saliva were 2-5 times higher than those in plasma shortly after drug administration. About 82% of the radioactivity was eliminated in the urine, 6% in expired air (as 14CO2) and 1% in feces. The major metabolite of LY 108380 (55% of the dose) was a quaternary amine formed by glucuronidation at the pyridine nitrogen. Less than 10% of the dose was N-demethylated to secondary and primary amines and about 2% was excreted unchanged.