The Neuromuscular Blocking Effects and Pharmacokinetics of ORG 9426 and ORG 9616 in the Cat

Abstract

The neuromuscular blocking effects and pharmacokinetics of ORG 9426, 1.5 mg/kg and ORG 9616, 1.2 mg/kg iv, two new nondepolarizing neuromuscular blocking drugs, were studied in 28 cats (i.e., 14 cats with each drug) with and without renal pedicle ligation. A gas chromatographic assay was used to determine the concentrations of ORG 9426 and ORG 9616 and its desacetyl metabolites in plasma, urine, bile, and liver. The duration of neuromuscular blockade of both drugs was not altered by ligation of renal pedicles. Plasma clearance of ORG 9426 was slower in cats with ligated renal pedicles (P < 0.01). With ORG 9616, mean elimination half-life was slower and mean residence time longer in cats with renal pedicle ligation. Otherwise, there was no significant differences with any pharmacokinetic variables in cats with and without renal pedicle ligation. Only 8.7 .+-. 5.7% (SD) and 6.0 .+-. 2.8% of an injected dose of ORG 9426 and ORG 9616 was excreted into the urine, respectively. Conversely, 54.4 .+-. 9.2% and 52.4 .+-. 9.2% of an injected dose of ORG 9426 and 35.7 .+-. 12.2% and 46.8 .+-. 9.7% of ORG 9616 were excreted into the bile in cats without and with renal pedicle ligation, respectively. Finally, 21.3 .+-. 6.5% and 33.5 .+-. 15.6% of ORG 9426 and 14.0 .+-. 3.2% and 18.1 .+-. 5.6% of ORG 9616 were in the liver 6 h after injection in cats without and with renal pedicle ligation respectively. The authors were able to account for the biodisposition of 84.4% and 85.9% of an injected dose of ORG 9426 in cats without and with renal pedicle ligation respectively. Becasue none of the desacetyl metabolites were detected in plasma, urine, bile, or liver, and most of the ORG 9426 was accounted for in the unchanged form, little or no metabolism apparently takes place. The authors conclude that ORG 9426 has an intermediate duration of action and is cleared from plasma primarily due to hepatic uptake and biliary excretion of the unchanged drug. In contrast, approximately 40% of the ORG 9616 recovered was in the form of its 3-desacetyl metabolite. However, the authors were able to recover only 55.7% and 64.6% of an injected dose of ORG 9616 with and without renal pedicle ligation, respectively. The authors concluded that ORG 9616 has a short duration of action and is cleared from plasma by metabolism and biliary excretion.