Pharmacokinetics and pharmacodynamics of vecuronium in rats with systemic inflammatory response syndrome - Treatment with N-G-monomethyl-L-arginine

Background: Insufficient detoxification caused by nitric oxide-related inhi bition of cytochrome P450 may be important for metabolism of numerous drugs , including vecuronium, The present study investigated the pharmacodynamics and pharmacokinetics of vecuronium in rats with inflammatory liver dysfunc tion. Methods: Male Sprague-Dawley rats (n = 56) were randomly allocated into two groups: In the sepsis group, liver inflammation was established by injecti on of 56 mg/kg heat-killed Corynebacterium parvum; control rats received th e solvent. At day 4, groups were subdivided according to treatment with the nitric oxide synthase inhibitor N-G-monomethyl-L-arginine (250 mg/kg) or p lacebo. The aminopyrine breath test was performed to assess cytochrome P450 activity. Rats mere anesthetized with propofol and mechanically ventilated . Duration of action of vecuronium (1.2 mg/kg) was measured by evoked mecha no-myography (stimulation of the sciatic nerve, contraction of the gastrocn emius muscle). In seven rats of each subgroup a 50% neuromuscular blockade was established by a continuous vecuronium infusion. Vecuronium plasma leve ls were measured and plasma clearance of vecuronium was calculated. Nitric oxide synthesis was assessed by measuring nitrite/nitrate serum levels. Results: In sepsis/placebo rats, vecuronium-induced neuromuscular blockade was prolonged (144% of control/placebo), vecuronium plasma levels at 50% ne uromuscular blockade were increased (122% of control/placebo), and plasma c learance was decreased (68% of control/placebo). N-G-monomethyl-L-arginine therapy in rats with sepsis improved cytochrome P450 activity and plasma cl earance of vecuronium, shortened duration of action of vecuronium, but did not alter the elevated vecuronium plasma levels. Conclusions: A systemic inflammatory response syndrome with liver dysfuncti on results in decreased sensitivity to and a decreased elimination of vecur onium, Modulation of nitric oxide synthesis may be a strategy that can be u sed in the future to improve xenobiotic metabolism in sepsis.