Adiphenine

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ALTHOUGH THE DRUG IS RELATIVELY NONTOXIC, IT SHOULD NOT BE USED IN CLOSE SEQUENCE WITH MORPHINE; THE COMBINATION APPEARS TO CAUSE APPREHENSION & TACHYCARDIA. /ADIPHENINE HYDROCHLORIDE/

Spasmolytin (adiphenine hydrochloride) and tropicine were administered im to albino rats poisoned with anabasine sulfate doses of 346, 519, and 692 mg/kg administered through gastric tube. The LD50 of anabasine sulfate, determined for treatment with adiphenine hydrochloride, was 570 mg/kg, and 403 mg/kg for treatment with tropacine. The LD16 and LD84 values determined for treatment with adiphenine hydrochloride and tropacine were 460 and 712 mg/kg and 288 and 498 mg/kg, respectively. Adiphenine hydrochloride and tropacine, administered im in 20 mg/kg doses, reduced the LD50 of anabasine sulfate by 271% and 191%, respectively./Adiphenine hydrochloride/

/ALTERNATIVE and IN VITRO TESTS/The mechanism of action of adiphenine on in vitro rat anterior pituitary TSH release was compared to that of the physiological stimulator TRH. The comparative study showed that adiphenine and TRH were able to increase TSH release in a dose-dependent manner, had similar time courses of action for equipotent stimulating concentrations and produced similar aspects of stimulated TSH cells. However, there were several differences between the effects of adiphenine and TRH. Adiphenine action was inhibited by 20 mM K+; was not calcium dependent; was inhibited by neither thyroid hormones nor somatostatin; was little affected by energy depression. It is concluded that adiphenine probably acts near the ultimate steps of the TSH release pathway and could be a useful pharmacological tool for studying the mechanism of TSH release.

Adiphenine was administered in 3H-labelled form in doses of 15 mumole/kg intravenously to male Wistar rats. Plasma and brain levels of the unchanged drug were measured. The elimination of the 3H-labelled compound from the plasma was monophasic with a half-life of 13 minutes. The unchanged drug was detectable in the plasma for 30 minutes after the injection. The time course of brain levels of unchanged drug paralleled that found in the plasma with a half-life of 9 to 12 minutes. In all experiments, brain and plasma levels of unchanged adiphenine correlate highly.

Major metabolites isolated from rat urine after administration of a single dose of (14C)adiphenine or (3H)adiphenine were identified by chromatography and n.m.r. spectrometry, and by comparison with authentic reference compounds chemically synthesized. Adiphenine was extensively metabolized by hydrolysis of the ester bond into diethylaminoethanol, diphenylacetic acid, diphenylacetic acid glucuronide and, in small quantities, the corresponding glycine and glutamine conjugates.

The disposition of adiphenine labelled with 14C in two positions has been investigated in rats and mice after iv administration ... In preliminary metabolic studies, three major metabolites have been identified: diphenylacetic acid, diethylethanolamine and a diphenylacetic acid glucuronide.

This study describes the behavior of a dual labelled drug, adiphenine, in the rat brain. Macroautoradiographies show images of the brain at different times after injection. Some of the tissue metabolites are identified at the brain level and the passage of the blood brain barrier is compared with tritiated water. The obtained data give very interesting indications on the blood brain distribution and on the metabolism at the brain level. Different techniques of high pressure liquid chromatography, macro- and histoautoradiographies allowed /visualization of/ how the drug is fixed on cerebral structures, giving indications on its mechanism of action.

The disposition of adiphenine labelled with 14C in two positions has been investigated in rats and mice after iv administration, and has been compared with that of the [14C]diethylethanolamine HCl and of the [14C]diphenylacetic acid. Radioactivity in the blood declined in a biphasic manner. Biliary elimination depended upon the 14C-labelled compound administered: less than 5% dose for the diethylethanolamine moiety, 100% dose for the carboxylic moiety. Of the radioactivity appearing in rat bile, less than 1% is associated with unchanged adiphenine. ... Uptake by the brain of [14C]adiphenine shortly after dosing is 15 times greater than that of blood. Radioactivity is also found in the hypophysis, the adrenals and melanoid pigments, with a concentration up to 30 times greater than that found in the blood.