Structure-pharmacodynamic-pharmacokinetic relationships of steroidal neuromuscular blocking agents. 1995

J M Wierda, and J H Proost
Research Group for Experimental Anesthesiology and Clinical Pharmacology, University Hospital, Groningen Institute for Drug Studies (GIDS), The Netherlands.

Several new steroidal non-depolarizing muscle relaxants have been synthesized and tested in humans recently. Results from these studies suggest that the differences in time-course of action between these compounds are mainly, if not totally, related to differences in biodisposition. Biodisposition, in turn, is determined largely by the physico-chemical characteristics of the drug, such as degree of lipophilicity and protein binding. The various pharmacodynamic and pharmacokinetic variables of a series of structurally related steroidal relaxants, varying in the ester substituent at the 17th position of the androstane skeleton, have been related to the degree of lipophilicity. Significant positive relationships could be shown between lipophilicity (logP at pH 7.4) and, among other things, potency (ED90), effective concentration (EC50), unbound plasma clearance (CLupl) and rate constant of transport between plasma and biophase (ke0). The aforementioned relationships between lipophilicity and pharmacokinetic variables resulted in significant 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 steroidal relaxants which enhance lipophilicity coincide with a decrease of (intrinsic) potency and a shorter time course of action. Protein binding appears to be of minor importance for the biodisposition and time 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 observed with rocuronium may in part result from its relatively high unbound fraction in plasma.

UI MeSH Term Description Entries
D008055 Lipids A generic term for fats and lipoids, the alcohol-ether-soluble constituents of protoplasm, which are insoluble in water. They comprise the fats, fatty oils, essential oils, waxes, phospholipids, glycolipids, sulfolipids, aminolipids, chromolipids (lipochromes), and fatty acids. (Grant & Hackh's Chemical Dictionary, 5th ed) Lipid
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D001798 Blood Proteins Proteins that are present in blood serum, including SERUM ALBUMIN; BLOOD COAGULATION FACTORS; and many other types of proteins. Blood Protein,Plasma Protein,Plasma Proteins,Serum Protein,Serum Proteins,Protein, Blood,Protein, Plasma,Protein, Serum,Proteins, Blood,Proteins, Plasma,Proteins, Serum
D002627 Chemistry, Physical The study of CHEMICAL PHENOMENA and processes in terms of the underlying PHYSICAL PHENOMENA and processes. Physical Chemistry,Chemistries, Physical,Physical Chemistries
D003473 Neuromuscular Nondepolarizing Agents Drugs that interrupt transmission at the skeletal neuromuscular junction without causing depolarization of the motor end plate. They prevent acetylcholine from triggering muscle contraction and are used as muscle relaxants during electroshock treatments, in convulsive states, and as anesthesia adjuvants. Curare-Like Agents,Curariform Drugs,Muscle Relaxants, Non-Depolarizing,Neuromuscular Blocking Agents, Competitive,Nondepolarizing Blockers,Agents, Curare-Like,Agents, Neuromuscular Nondepolarizing,Blockers, Nondepolarizing,Curare Like Agents,Drugs, Curariform,Muscle Relaxants, Non Depolarizing,Non-Depolarizing Muscle Relaxants,Nondepolarizing Agents, Neuromuscular
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000293 Adolescent A person 13 to 18 years of age. Adolescence,Youth,Adolescents,Adolescents, Female,Adolescents, Male,Teenagers,Teens,Adolescent, Female,Adolescent, Male,Female Adolescent,Female Adolescents,Male Adolescent,Male Adolescents,Teen,Teenager,Youths
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D000368 Aged A person 65 years of age or older. For a person older than 79 years, AGED, 80 AND OVER is available. Elderly

Related Publications

J M Wierda, and J H Proost
January 1975, Advances in drug research,
J M Wierda, and J H Proost
August 2002, Current medicinal chemistry,
J M Wierda, and J H Proost
November 2006, Advanced drug delivery reviews,
J M Wierda, and J H Proost
February 1987, Clinical pharmacokinetics,
J M Wierda, and J H Proost
May 2016, Chemical biology & drug design,
J M Wierda, and J H Proost
January 1988, Acta anaesthesiologica Belgica,
J M Wierda, and J H Proost
February 1981, Journal of pharmacokinetics and biopharmaceutics,
J M Wierda, and J H Proost
June 1973, Chemico-biological interactions,
J M Wierda, and J H Proost
February 1989, Clinical pharmacokinetics,
Copied contents to your clipboard!