Pharmacokinetics and pharmacodynamics of vecuronium in rats with systemic inflammatory response syndrome: treatment with NG-monomethyl-L-arginine.
BACKGROUND
Insufficient detoxification caused by nitric oxide-related inhibition 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 dysfunction.


METHODS
Male Sprague-Dawley rats (n = 56) were randomly allocated into two groups: In the sepsis group, liver inflammation was established by injection of 56 mg/kg heat-killed Corynebacterium parvum; control rats received the 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 placebo. The aminopyrine breath test was performed to assess cytochrome P450 activity. Rats were anesthetized with propofol and mechanically ventilated. Duration of action of vecuronium (1.2 mg/kg) was measured by evoked mechanomyography (stimulation of the sciatic nerve, contraction of the gastrocnemius muscle). In seven rats of each subgroup a 50% neuromuscular blockade was established by a continuous vecuronium infusion. Vecuronium plasma levels 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 contro/placebo), vecuronium plasma levels at 50% neuromuscular blockade were increased (122% of control/placebo), and plasma clearance was decreased (68% of control/placebo). N(G)-monomethyl-L-arginine therapy in rats with sepsis improved cytochrome P450 activity and plasma clearance 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 dysfunction results in decreased sensitivity to and a decreased elimination of vecuronium. Modulation of nitric oxide synthesis may be a strategy that can be used in the future to improve xenobiotic metabolism in sepsis.
Blobner
M
M
Institut für Anaesthesiogie der Technischen Universität München, Kinikum rechts der Isar, Munich, Germany. manfred.blobner@lrz.tum.de
Kochs
E
E
Fink
H
H
Mayer
B
B
Veihelmann
A
A
Brill
T
T
Stadler
J
J
D000410:Alanine Transaminase / Q000096:biosynthesis; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D006520:Hepatitis, Animal / Q000201:enzymology / Q000378:metabolism; D008658:Inactivation, Metabolic; D008297:Male; D003473:Neuromuscular Nondepolarizing Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D011425:Propionibacterium acnes; D051381:Rats; D017207:Rats, Sprague-Dawley; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D014673:Vecuronium Bromide / Q000493:pharmacokinetics* / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003473:Neuromuscular Nondepolarizing Agents; D009569:Nitric Oxide; D014673:Vecuronium Bromide; D003577:Cytochrome P-450 Enzyme System; D000410:Alanine Transaminase