MECHANISMS UNDERLYING THE PROLONGED DURATION OF ACTION OF MUSCLE RELAXANTS CAUSED BY EXTRAHEPATIC CHOLESTASIS

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Abstract
The neuromuscular blocking effects of Org 6368 and Org NC 45 were studied in rats with experimental cholestasis and in controls. The effect of Org NC 45 during infusion of taurocholate was investigated. In cholestaic rats we observed a three-fold increase of the duration of action of Org 6368 and Org NC 45. The same was observed for Org NC 45 with taurocholate. In the rat phrenic nerve-hemidiaphragm preparation taurocholate potentiated the neuromuscular blockade of Org 6368, pancuronium and gallamine, but not Org NC 45. Increased bile salt concentrations caused strong inhibition of hepatic uptake and biliary excretion of Org 6368 and tubocurarine in isolated perfused livers. Taurocholate and glycocholate were more potent than cholate and chenodeoxycholate. Cholestatic livers exhibited a clearance of Org 6368 which was 50% of control. We conclude that the prolonged duration of action of certain muscle relaxants because of cholestasis results from both inhibition of hepatic uptake by the accumulated bile salts and a general deterioration of liver transport function.