Physicochemical properties of neuromuscular blocking agents and their impact on the pharmacokinetic-pharmacodynamic relationship.
BACKGROUND
Among the factors influencing the onset of action of neuromuscular blocking agents (NMBA), the potency (EC50) and the rate of equilibration between blood and the effect compartment (k(e0)) have been highlighted. Although these descriptors are intrinsically influenced by the physicochemical characteristics of the drug, the impact of lipid solubility, molecular weight and protein binding on pharmacokinetic-pharmacodynamic (PK-PD) descriptors has not been established for most NMBA.


METHODS
The octanol/phosphate buffer distribution coefficients (logD) of various NMBA (vecuronium, rocuronium, mivacurium isomers (cis-cis, cis-trans and trans-trans), doxacurium, cisatracurium, atracurium, succinylcholine) were determined. The free fraction for each drug was measured using an ultrafiltration technique. PK-PD descriptors were obtained from selected clinical studies. Correlations between physicochemical parameters (including molecular weight) and PK-PD descriptors were assessed by linear or multiple linear regression.


RESULTS
A wide range of log D (-4.15 for succinylcholine to 0.75 for vecuronium) and free fraction (from 31% for vecuronium to 80% for succinylcholine) is observed for NMBA. Molecular weight combined with either lipid solubility (r2=0.70; P=0.001) or free fraction (r2=0.84; P<0.001) were highly correlated with potency, while for k(e0) a greater degree of correlation was obtained when both lipid solubility and free fraction (r2=0.74; P=0.002) were included.


CONCLUSIONS
The basic characteristics of NMBAs, namely, molecular weight, lipid solubility and protein binding, are strongly associated with the kinetics of the drug response.
Roy
J J
JJ
Faculté de pharmacie, Université de Montréal, 2900 boul. Edouard Montpetit, C.P. 6128, Succursale Centre-ville, Montréal (Québec), H3C 3J7, Canada.
Varin
F
F
D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D050356:Lipid Metabolism; D008970:Molecular Weight; D009466:Neuromuscular Blocking Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D009467:Neuromuscular Depolarizing Agents / Q000737:chemistry; D003473:Neuromuscular Nondepolarizing Agents / Q000737:chemistry; D011485:Protein Binding; D012995:Solubility
D009466:Neuromuscular Blocking Agents; D009467:Neuromuscular Depolarizing Agents; D003473:Neuromuscular Nondepolarizing Agents