To obtain more insight in the relation between physicochem. properties of neuromuscular blocking agents (NMBAs) and their pharmacokinetic characteristics, a series of 12 aminosteroidal NMBAs, supplemented with data on five related NMBAs from the literature, was investigated in anesthetized cats.After i.v. bolus injection, plasma concentration decreased very rapidly, showing a biphasic pattern, with half-lives ranging from 0.4 to 1.4 min, and from 3 to 10 min, resp.Clearance was in the range from 24 to 58 mL · min^-1 · kg^-1.Compounds containing an acetyl-ester group at position 3 were partly metabolized to the 3-OH derivativeThe urinary excretion of the parent drug and metabolites amounted to <10% for each of the compoundsThe parent drugs were excreted in large amounts into bile, along with smaller amounts of 3-OH derivativesThe terminal half-life of the urinary and biliary excretion rate were markedly longer than the apparent terminal half-life in plasma, ranging from 11 to 40 min, and from 119 to 489 min in urine and bile, resp.Lipophilicity of the NMBAs, expressed as the partition coefficient octanol/Krebs (log P), was correlated pos. with unbound plasma clearance and unbound initial plasma clearance, and neg. with plasma half-life, volume of distribution at steady state, and mean residence time.The increase of the unbound plasma clearance with increasing lipophilicity is counteracted by the concurrent increase in plasma protein binding.

01 Aug 1997·The Journal of Pharmacology and Experimental Therapeutics

Relationship between Chemical Structure and Physicochemical Properties of Series of Bulky Organic Cations and Their Hepatic Uptake and Biliary Excretion Rates

Author: Proost, Johannes H. ; Meijer, Dirk K. F. ; Wierda, J. Mark K. H. ; Roggeveld, Jan

To obtain more insight in the relation between physicochem. properties of cationic drugs and their hepatobiliary transport rate, a series of 12 aminosteroidal neuromuscular blocking agents (NMBAs), supplemented with data of four related NMBAs from the literature, were investigated in the isolated perfused rat liver.A significant correlation was found between plasma protein binding and the partition coefficient octanol/Krebs (log P), confirming results from the literature with other organic cations.Evidence was found for a saturable hepatic uptake of several NMBAs, indicating that carrier-mediated uptake processes are involved.Hepatic uptake rate was closely related to the lipophilicity of the compounds; the initial extraction ratio, the apparent clearance and the intrinsic clearance were significantly correlated to log p.We did not find a significant correlation between biliary clearance and lipophilicity in the current series of compoundsPharmacokinetics anal. of perfusate disappearance and biliary excretion data revealed that a considerable fraction of the dose of these bulky organic cations is stored in the liver and seems to not be directly available for biliary excretion.This finding is in line with earlier observations showing a pronounced accumulation of this type of compounds in mitochondria and lysosomes.

01 Nov 1994·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

In-vitro Smooth Muscle Relaxant Activity of a Series of Vecuronium Analogues in the Rat Aorta

Q3 · MEDICINE

Article

Author: Prior, Chris ; Fiddes, Shaun

AbstractThe ability of a series of 17-ester analogues of vecuronium to elicit a direct relaxant effect on vascular smooth muscle has been studied using rat isolated aortic rings contracted with 40 mm KCl. The IC50 for inhibition of KCl-induced contractions increased with increasing size of the 17-ester substituent, such that vecuronium (17β-acetate) was the least potent with an IC50 of around 500 μm and Org-9827 (17α-pivalate) was the most potent with an IC50 of around 5 μm. In addition, for the weaker-acting compounds, the 17α-esters were more potent than their corresponding 17β-esters, although this difference was lost as the size of the 17-ester substituent increased. From the results obtained here, it is concluded that the hypotensive activity of some of the newer neuromuscular blocking steroids seen in cats, pigs and dogs in-vivo is probably, at least in part, a consequence of a direct relaxant effect of the compound on vascular smooth muscle through inhibition of voltage-activated, L-type, calcium channels. This may have both advantageous and disadvantageous clinical consequences when using large doses of one of the newer vecuronium analogues with a low relative neuromuscular-blocking potency.

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Indication	Highest Phase	Country/Location	Organization	Date
Reversal of Neuromuscular Blockade	Phase 1	-	Akzo Nobel NV	-

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