T. Tajima (1)
(1) Novartis Pharma K.K., Tokyo
Objectives: Neuromuscular relaxants exert the pharmacological effect blocking nicotinic receptors at neuromuscular junction. For the pharmacodynamics, 1) in vitro affinity for receptor and in vivo potency are neither in concord nor in a proportional relationship; Even for a drug with high affinity, a substantial concentration is needed to evoke the blockade effect, 2) the slop of dose-effect curve or concentration-effect curve is different among drugs, suggesting a drug with higher affinity has a steeper slop. In this study, the underlying mechanisms were investigated using a dynamic model based on physiological and pharmacological mechanisms.
Methods: A dynamic model was developed taking into account: i) released transmitter acetylcholine (ACh) binds to receptor and evokes muscle contraction, ii) tension of muscle contraction depends on receptor occupancy by ACh, iii) a relaxant binds to receptor competitively inhibiting receptor binding of ACh and depresses muscle tension. Concentration-effect curves were simulated for drugs with various dissociation constants of drug-receptor complex (Kc). Relationship of Kc with EC50 and apparent slop (γ) of concentration-effect curves was investigated.
Results: Drugs with Kc of 0.001, 0.01, 0.1 and 1.0 μM show EC50 of 0.146, 0.285, 1.70 and 15.8 μM, and γ of 11.8, 6.84, 5.19 and 5.00, respectively. Comparing drugs with low affinity (Kc=1.0) and moderate affinity (Kc=0.1), the difference of Kc is almost proportionally reflected in EC50 and has little impact on γ. However, with increasing affinity (decreasing Kc), Kc is under-proportionally reflected in EC50 and γ increases. Receptor density (about 0.2 μM) is a responsible factor. Drugs need to occlude receptors to exert the effect. So, even a drug with high affinity needs concentrations close to receptor density, and EC50 does not become so small. Further, for a drug with high affinity, the amount of drug binding to receptors is non-negligible relative to the total amount of drug in the action site. Free concentration dose not approximate total concentration, which causes the change of slope.
Conclusions: A mechanism-based dynamic model provided convincing explanations. Regarding not only muscle relaxants but also other therapeutic drugs blocking relevant receptors, the pharmacodynamics might be affected by affinity for receptor and receptor density when receptors densely locate in the action sites.
Reference: PAGE 21 (2012) Abstr 2311 [www.page-meeting.org/?abstract=2311]
Poster: Other Drug/Disease Modelling