The Relationship between Disposition and Duration of Action of a Congeneric Series of Steroidal Neuromuscular Blocking Agents

Abstract

The renal and hepatic elimination and biotransformation, as well as the relation between disposition and duration of action of pancuronium and two of its analogues, dacuronium and ORG.6368, have been investigated in the cat. In pharmacokinetic studies, appreciable amounts of the latter two compounds were found in the urine, bile and liver 8 h after their intravenous administration. Various proportions of the injected dose of the respective drugs were metabolized. In another series of experiments it was shown that the early hepatic uptake (during the first 3 min after the injection) of ORG.6368 was significantly greater than that of dacuronium and pancuronium. The intensity and duration of action of the neuromuscular blocking effect of the three compounds were studied after intravenous and "close" intraarterial injection. On the basis of these pharmacokinetic and neuromuscular studies, it was concluded that the short duration of action of ORG.6368 is due primarily to its early hepatic uptake. The possibility cannot be excluded, however, that differences in the kinetics of the drug action of ORG.6368 and the other two compounds also contributed significantly to the differences seen in the duration of action of these compounds.

Clinical Pharmacokinetics of Neuromuscular Blocking Drugs

“…The other approach (rapid termination of ef-105 fects by tissue uptake) is based on early observations showing that the liver can extract and store substantial amounts of quaternary ammonium steroids from the circulation (Agoston et al 1977). Subsequent studies (Meijer 1977;Upton et al 1981) contributed to the understanding of various structural and physicochemical properties governing the early distribution, including rapid hepatic uptake of this class of agents, and led to the introduction of vecuronium (Agoston et al 1980) and rocuronium (Wierda et al 1990b) [ fig.…”

“…The fetal arteriovenous concentration difference suggests appreciable uptake of pancuronium by the fetus. Hepatic uptake, an important mechanism of elimination of quaternary aminosteroids (Agoston et al 1977), may be important in the disposition (first-pass effect) of pancuronium, since the fetal liver receives approximately 50% of the umbilical blood flow. The lack of difference between VV and V A concentrations of pancuronium observed by Abouleish et al (1980) is surprising and the investigators did not comment on it.…”

Effect of Experimental Cholestasis on Neuromuscular Blocking Drugs in Cats

“…In the case of the neuromuscular blocking drugs tubocurarine (Cohen, Brewer and Smith, 1967;Meijer and Scaf, 1968;Meijer et al, 1979), pancuronium (Agoston et al, 1973;Buzello, 1975) and hexafluorenium (Meijer, Vermeer and Kwant, 1971), hepatic uptake and secretion appear to be major factors in determining the plasma concentrations. In the cat, hepatic uptake is an important factor in the plasma clearance of a number of steroid neuromuscular blocking agents, such as pancuronium, dacuronium and Org 6368 (Agoston, Kersten and Meijer, 1973;Agoston et al, 1977).…”

“…Three compounds, known to differ considerably in their elimination pathways (i.e. renal or biliary), were studied: Org 6368, the bisquaternary ammonium compound (2£,16$,-dipiperidino-5a-androstan-3a-ol acetate dimethobromide) differing from pancuronium only in lacking the acetate group at C17 position in the steroid skeleton and having a short duration of action in the cat (Sugrue and Duff, 1973), mainly as a result of a rapid hepatic uptake (Agoston et al, 1977); gallamine triethiodide, which in dog and man is predominantly eliminated by the kidneys (Mushin et al, 1949;Feldman, Cohen and Golling, 1969;Agoston et al, 1978); pancuromum, which in cat and man is eliminated by both urinary and binary routes (Agoston, Kersten and Meijer, 1973;Agoston et al, 1973).…”

The Placental Transfer of Pancuronium and Its Pharmacokinetics during Caesarian Section

“…Uptake occurs in many tissues but i s greatest in liver, as demonstrated by autoradiographic studies in mice (WASER 1973). I n human liver biopsies, obtained from eight patients during abdominal surgery, we have found pancuronium concentrations 2 to 5 times higher than those measured simultaneously in plasma samples using the same fluorimetric method of measurement, Liver uptake has been shown to play an important role in the disposition of steroidal blocking agents (AGOSTON et al 1977a) and appears to be a reasonable explanation for the cord venous-cord arterial difference in pancuronium concentration. The umbilical arterial concentration of pancuronium, which was about 44% lower than in the umbilical vein, is probably a better indicator of the concentration of pancuronium delivered to the muscle end-plates.…”