We have demonstrated that morphine slows hepatobiliary elimination of sulfobromophthalein (BSP) and other dyes in rats and mice. This effect on BSP is not entirely mediated by morphine-induced hypothermia, respiratory depression or biliary spasm. Competition by morphine for BSP transport could not be shown nor did the narcotic alter biotransformation of the dye. While narcotic did not affect enzymes related to BSP disposition, it did reduce metabolic clearance of lidocaine and antipyrine. Narcotics raised plasma levels and increased toxicity of acetaminophen, adriamycin and lidocaine. We plan to extend our studies of mechanisms and sites involved in hepatic actions and toxic interactions of narcotics. In studying hepatic blood flow, we will avoid acute anesthesia and abdominal surgery, which modify this parameter. Hepatic blood flow determines bioavailability of drugs given intravenously but not when given into the portal circulation. Pharmacokinetics of portally (peritoneal) and systemically (venous) administered drugs (lidocaine and propranolol) will be compared in rats given saline or morphine. Changes in regional distribution of radiolabelled microspheres and in arterial blood pressure will be studied. Narcotics act at receptors throughout the body. Intrathecal morphine was 200 times more potent than by other routes in reducing BSP clearance. To further define opioid sites affecting the liver, narcotics, their antagonists and corresponding polar analogues will be given to rodents by venous, peritoneal, spinal and cerebroventricular injections. Nerve pathways will also be lesioned to separate central from peripheral effects. Tolerance in mice will be produced by subcutaneous insertion of morphine pellets. After pellet removal, dose response relationships will be done for morphine effects on BSP disposition. Clonidine effects on BSP will be examined during acute narcotic withdrawal. After establishing safety in animals, studies between narcotics and cardiac drugs will be started in patients. Hepatic blood flow will be evaluated in patients receiving fentanyl anesthesia by measuring disappearance of indocyanine green from plasma. Future studies of narcotic effects on disposition, efficacy and toxicity of antineoplastic drugs, like adriamycin, are planned.
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