The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Nov 2000
Altered hepatobiliary disposition of acetaminophen glucuronide in isolated perfused livers from multidrug resistance-associated protein 2-deficient TR(-) rats.
Previous studies have demonstrated that phenobarbital treatment impairs the biliary excretion of acetaminophen glucuronide (AG), although the transport system(s) responsible for AG excretion into bile has not been identified. Initial studies in rat canalicular liver plasma membrane vesicles indicated that AG uptake was stimulated modestly by ATP, but not by membrane potential, HCO(3)(-), or pH gradients. To examine the role of the ATP-dependent canalicular transporter multidrug resistance-associated protein 2 (Mrp2)/canalicular multispecific organic anion transporter (cMOAT) in the biliary excretion of AG, the hepatobiliary disposition of acetaminophen, AG, and acetaminophen sulfate (AS) was examined in isolated perfused livers from control and TR(-) (Mrp2-deficient) Wistar rats. ⋯ AG and AS perfusate concentrations were significantly higher in livers from TR(-) compared with control rats. Pharmacokinetic modeling of the data revealed that the rate constant for basolateral egress of AG increased significantly from 0.028 to 0.206 min(-1), consistent with up-regulation of a basolateral organic anion transporter in Mrp2-deficient rat livers. In conclusion, these data indicate that AG biliary excretion is mediated by Mrp2, and clearly demonstrate that substrate disposition may be influenced by alterations in complementary transport systems in transport-deficient animals.
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J. Pharmacol. Exp. Ther. · Nov 2000
Analgesic synergy between topical lidocaine and topical opioids.
Topical drugs avoid many of the problematic side effects of systemic agents. Immersion of the tail of a mouse into a solution of dimethyl sulfoxide (DMSO)-containing morphine produces a dose-dependent, naloxone-sensitive, analgesia (ED(50) 6.1 mM; CL 4.3, 8.4) limited to the portion of the tail exposed to the drug. DMSO alone in this paradigm had no analgesic activity. ⋯ Combinations of a low dose of lidocaine with a low dose of an opioid yielded significantly greater than additive effects for all opioids tested. Isobolographic analysis confirmed the presence of synergy between lidocaine and morphine, levorphanol and buprenorphine. These studies demonstrate a potent interaction peripherally between opioids and a local anesthetic and offer potential advantages in the clinical management of pain.