STRUCTURE-PHARMACODYNAMIC-PHARMACOKINETIC RELATIONSHIPS OF STEROIDAL NEUROMUSCULAR BLOCKING-AGENTS

Several new steroidal non-depolarizing muscle relaxants have been synt hesized and tested in humans recently. Results from these studies sugg est that the differences in time-course of action between these compou nds are mainly, if not totally, related to differences in biodispositi on. Biodisposition, in turn, is determined largely by the physico-chem ical characteristics of the drug, such as degree of lipophilicity and protein binding. The various pharmacodynamic and pharmacokinetic varia bles of a series of structurally related steroidal relaxants, varying in the ester substituent at the 17th position of the androstane skelet on, have been related to the degree of lipophilicity. Significant posi tive relationships could be shown between lipophilicity (logP at pH 7. 4) and, among other things, potency (ED(90)), effective concentration (EC(50)), unbound plasma clearance (CLupt) and rate constant of transp ort between plasma and biophase (k(eo)). The aforementioned relationsh ips between lipophilicity and pharmacokinetic variables resulted in si gnificant inverse relationships between lipophilicity and time course parameters, such as onset time and duration of neuromuscular blocking effects. It is concluded that changes in the molecular structure of st eroidal relaxants which enhance lipophilicity coincide with a decrease of (intrinsic) potency and a shorter time course of action. Protein b inding appears to be of minor importance for the biodisposition and ti me course characteristics, since there were only small differences in degree of protein binding between most of the investigated compounds. However, the surprisingly fast initial rate of block development obser ved with rocuronium may in part result from its relatively high unboun d fraction in plasma.