Background:

Ro 24-4736 is a potent, selective, p.o.-active platelet-activating factor (PAF) antagonist with a long duration of action.

Ro 24-4736 competes with [3H]PAF for its receptor site on dog platelets with an IC50 of 9.8±1.0 nM and selectively inhibits PAF-induced aggregation of guinea pig, dog and human platelets with concentration dependence[1].

Ro 24-4736 dose-dependently inhibits in vivo bronchoconstriction (ID50 of 0.006-mg/kg p.o.) and ex vivo platelet aggregation (ID50 of 0.004 mg/kg p.o.) induced by PAF in guinea pigs. Time course studies show complete blockade of PAF-induced platelet aggregation (ex vivo) up to 8 hr after a single p.o. dose of 0.03 mg/kg as well as a long duration of action in vivo (30 hr). The in vivo PAF antagonistic activity is specific because, even at high p.o. doses (up to 10 mg/kg), Ro 24-4736 shows no inhibitory activity toward the bronchoconstrictor effects of leukotriene D4 or histamine. In comparison with other PAF antagonists evaluated in this guinea pig model, Ro 24-4736 is markedly superior in terms of p.o. potency, bioavailability and p.o. duration of action. Studies are also performed with Ro 24-4736 in additional in vivo models. When administered p.o. to sensitized guinea pigs, the drug attenuates inhaled antigen-induced airway hyper-reactivity without effect on bronchoalveolar lavage leukocyte accumulation[1]. Ro 24-4736 is a new platelet activating factor antagonist. The tissue distribution of the 14C-label in male rats following a single intravenous dose of 1.0 mg/kg of 14C-Ro 24-4736 indicats appreciable uptake by the liver, kidney, heart and gastrointestinal tract. Peak plasma and tissue concentrations are seen at 5 minutes after dosing except for the small intestine (4 hrs) and abdominal fat, stomach and large intestine (4 hrs). At 48 hours, only 3.5% of the dose is present in the tissues, and 6.1% in the lumen of the gastrointestinal tracts[2].

[1]. Crowley HJ, et al. Pharmacology of a potent platelet-activating factor antagonist: Ro 24-4736. J Pharmacol Exp Ther. 1991 Oct;259(1):78-85. [2]. Anastasi EM, et al. Disposition and metabolism of Ro 24-4736 in the rat. Life Sci. 1994;54(26):PL483-90.