Pharmacokinetic origin of carbamazepine-induced resistance to vecuronium neuromuscular blockade in anesthetized patients.

BACKGROUND: Patients receiving chronic carbamazepine therapy have shortened recovery times from a neuromuscular block induced by vecuronium. The current study investigates the pharmacokinetic or pharmacodynamic mechanisms responsible for this observation. METHODS: Pharmacokinetics and pharmacodynamics of 0.1 mg/kg intravenous bolus vecuronium in ten epileptic patients receiving chronic carbamazepine therapy were compared to that of ten control subjects. All patients were scheduled for neurosurgery while anesthetized with isoflurane and sufentanil. Arterial blood samples were collected for 6 h. Plasma vecuronium concentrations were measured by high-performance liquid chromatography coupled to electrochemical detection. The adductor pollicis force of contraction was recorded after supramaximal ulnar nerve stimulation. Plasma vecuronium concentrations were fitted to a two-compartment pharmacokinetic model, and the effect compartment equilibration rate constant was derived with a nonparametric link model. The effect compartment concentrations were fitted to a sigmoid Emax model. Results were compared using Student's t-test for independent samples. RESULTS: In the carbamazepine group, the mean recovery times to T(1) 25% were shorter (28.1 +/- 3.4 vs. 47.3 +/- 5.1 min in control subjects; P=0.007), and the T(1) 25% to T(1) 75% recovery index was decreased (7.6 +/- 1.2 vs. 21.9 +/- 6.8 min in control subjects; P=0.025). No changes in onset times were observed. Clearance was 9.0 +/- 1.2 ml x kg-1 x min-1 versus 3.8 +/- 0.3 in the control group (P=0.003), whereas no changes in volumes of distribution at steady-state were observed. Therefore, the mean residence time was halved (17.8 +/- 2.5 vs. 31.9 +/- 2.5 min in control subjects; P=0.001). No differences in the effect compartment equilibration rate constant, vecuronium effect compartment concentration present at a 50% block (EC50), or slope of the sigmoid between the two groups were found. CONCLUSIONS: The twofold increase in clearance provides evidence of a pharmacokinetic origin to the carbamazepine-vecuronium interaction; however, the possibility of a concurrent pharmacodynamic alteration cannot be assessed. Greater knowledge of protein drug binding needs to be acquired to give a meaningful interpretation to the similar EC50 values observed in the two groups.