MECHANISMS OF NON-DROWSINESS AFTER ORAL-ADMINISTRATION OF TMK688, A NOVEL ANTIALLERGIC DRUG

The mechanisms of non-drowsiness after oral administration of TMK688 ( 1-[{5'-(3''-methoxy-4''- ethoxycarbonyloxyphenyl)-2',4'-pentadienoyl} aminoethyl]-4- diphenylmethoxypiperidine, CAS 110501-66-1) were invest igated using mice. TMK688 inhibited the histamine-induced vascular per meability at oral doses of 3.2-10 mg/kg with an ID50 value of 5.4 mg/k g. More than 100 times higher doses were needed to prolong the hexobar bital-induced sleeping. Pyrilamine, a typical antihistamine agent, sho wed little difference among these doses and antiallergic drugs having antihistamine activity, i.e., terfenadine, azelastine and ketotifen, h ad effects between TMK688 and pyrilamine. The inhibitory activity of o rally administered TMK688 against ex vivo [H-3]-pyrilamine binding to mouse cerebral histamine receptors appeared at the same doses as its p otentiating activity against hexobarbital-induced sleeping. When given orally, TMK688 was hydrolyzed to TMK777 (CAS 101619-11-8), then conju gated with glucuronic acid to TMK777-glucuronide. No TMK688 was detect ed in the blood. The main metabolite TMK777-glucuronide could hardly p enetrate the blood-brain barrier because of its polarity. Although the plasma concentrations of TMK777 were far lower than those of TMK777-g lucuronide, TMK777 was penetrable into the brain and the cerebral conc entrations of TMK777 increased in parallel with the plasma concentrati ons of the drug. Since intracerebroventricularly-injected TMK777 prolo nged the sleeping time, and since the threshold concentration of TMK77 7 in the cerebral cortex to potentiate the hexobarbital-induced sleepi ng was consistent despite different administration routes, the drowsin ess elicited by markedly high doses of TMK688 is though to be caused b y intracerebral TMK777. In other words, TMK688 does not seem to cause drowsiness at effective doses because of the poor prenetrability of it s main metabolites into the brain.