MEN Montelukast Zafirlukast and Pranlukast antagonized

MEN91507, Montelukast, Zafirlukast, and Pranlukast antagonized leukotriene D4-induced bronchoconstriction in guinea-pigs, following both intravenous and oral administration. When administered intravenously, MEN91507 was the most potent amongst the CysLT1 receptor antagonists tested, since the ED50s for Montelukast, Pranlukast, and Zafirlukast were about 2, 10 and 20 times greater than that of MEN91507. Following oral administration Montelukast was slightly (but non-significantly) more potent of MEN91507, whereas the ED50s of Pranlukast and Zafirlukast were 8 and 11 fold greater than that of MEN91507. The protection afforded by oral administration of MEN91507, Montelukast, and Pranlukast against leukotriene D4-induced bronchoconstriction was long-lasting, since after 8 h this response was still substantially antagonized. Therefore, although following the oral route of administration the absolute potency of MEN91507 and Montelukast was greater than that of Pranlukast, the duration of the anti-bronchoconstrictor effect of the latter D4476 was relatively longer than that of both MEN91507 and Montelukast. In addition to the blockade of airway smooth muscle contractions, CysLT1 receptor antagonists also exerted a potent anti-inflammatory effect at this level. The oral administration of MEN91507, Pranlukast, Montelukast, and Zafirlukast also produced a long-lasting inhibition of leukotriene D4-induced microvascular leakage. Again, no significant differences were observed in the duration of the anti-inflammatory effect of these antagonists. Differences in the potencies of various antagonists in blocking different effects induced by the same agonist (e.g., leukotriene D4-induced bronchoconstriction vs. plasma leakage) are not uncommon and could be due to a differential distribution of the drug in the target tissues. The affinity of MEN91507, Montelukast, Zafirlukast, and Pranlukast, for CysLT1 receptors in guinea-pig lung membranes is comparable, therefore the higher potency of MEN91507 in inhibiting leukotriene D4-induced bronchoconstriction following the i.v. administration could be indicative of a greater metabolic stability, lower excretion rate, or differential tissue distribution as compared to the other CysLT1 receptor antagonists. In human tissue (dU937 cells), the affinity of Zafirlukast (Ki=0.73 nM) and Pranlukast (Ki=0.64 nM) was comparable to that of MEN91507 (Ki=0.65 nM) and Montelukast (Ki=0.60 nM). However, oral doses of 10, 40, and 450 mg/die are respectively needed for Montelukast, Zafirlukast, and Pranlukast to exert a therapeutic effect in asthmatic patients Markham and Faulds, 1998, Roquet et al., 1997, Tomari et al., 2001. Therefore, although Montelukast was the most potent CysLT1 receptor antagonist after oral administration in both humans and guinea-pigs, the oral effective doses of Pranlukast and Zafirlukast greatly diverge in humans, whereas they are similar in guinea-pigs. Even when considering Montelukast only, its oral bioavalability seems higher in humans than in guinea-pigs (see above), since an oral dose of 10 mg produced a clinical effect that was comparable to an intravenous dose of 7 mg (Dockhorn et al., 2000). All these results indicate the presence of important species-related differences in the pharmacokinetic, metabolic, and absorptive properties amongst different chemical classes of CysLT1 receptor antagonists.