Table 2—

Model parameters used to stimulate effect of Ono-AE2-227 on prostaglandin E2-induced inhibition of lipopolysaccharide stimulated tumour necrosis factor-α release from alveolar macrophages

Control10 nM100 nM1000 nM
Em %100100100100
KA130 nM210 nM1.8 μM21 μM
KA2 μM1111
  • E-prostanoid (EP)4 is receptor 1, EP2 is receptor 2 in this model. Em: maximum possible effect in the system. e1 = ϵ1R1 and e2 = ϵ2R2, where ϵ is intrinsic efficacy and R is receptor concentration. KA1 and KA2 are the dissociation constants of the agonist for the two receptors. To simulate the addition of Ono-AE2-227, KA1 is multiplied by the factor (1+[B]/KB1), where [B] is 10, 100 or 1,000 nM and KB1 is 0.67 nM (as estimated from the experiments in EP4 transfected human embryonic kidney cells). This factor was also corrected for the protein binding of Ono-AE2-227, which was measured as ∼99.8% in human plasma. The effective concentrations of [B] in the presence of 0.5% volume (v)/v FCS were, therefore, 4, 40 and 480 nM. KA2 is constant, as Ono-AE2-227 does not bind to EP2 receptors, i.e. the factor (1+[B]/KB2) = 1 at all concentrations used.