Physicochemical properties of neuromuscular blocking agents and their impact on the pharmacokinetic–pharmacodynamic relationship

• Published in: British journal of anaesthesia : BJA Vol. 93; no. 2; pp. 241 - 248
• Main Authors: Roy, J.J., Varin, F.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.08.2004; Oxford University Press; Oxford Publishing Limited (England)
• Subjects: agents; Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; binding; Biological and medical sciences; Chemical Phenomena; Chemistry, Physical; Humans; lipid; Lipid Metabolism; Medical sciences; Molecular Weight; neuromuscular block; neuromuscular block, agents; Neuromuscular Blocking Agents - chemistry; Neuromuscular Blocking Agents - pharmacokinetics; Neuromuscular Depolarizing Agents - chemistry; Neuromuscular Nondepolarizing Agents - chemistry; pharmacokinetics; pharmacokinetics, potency; potency; protein; Protein Binding; Solubility; solubility, lipid; solubility, lipid; neuromuscular block, agents; protein, binding; pharmacokinetics, potency; Phosphates; neuromuscular block; Linear regression; Solubility; agents; pharmacokinetics; potency; protein; lipid; Isomer; Neuromuscular blocking agent; binding; solubility; Binding protein; Ultrafiltration; Anesthesia; Pharmacokinetics; Physicochemical properties
• ISSN: 0007-0912; 1471-6771
• DOI: 10.1093/bja/aeh181

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 (ke0) 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. 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. 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 ke0 a greater degree of correlation was obtained when both lipid solubility and free fraction (r2=0.74; P=0.002) were included. The basic characteristics of NMBAs, namely, molecular weight, lipid solubility and protein binding, are strongly associated with the kinetics of the drug response.