A Disposition Kinetic Study of Tramadol in Intoxicated Rats Induced by Ethanol and Acetaminophen in Perfused Rat Liver Model.

Damage to the liver can lead to changes in the metabolism of tramadol. In this study, the rate of tramadol metabolites in rats with damaged liver induced by ethanol and acetaminophen were assessed in a recirculation perfusion system. Tramadol hydrochloride (TrHC) is a central nervous system (CNS) acting synthetic analgesic drug having both opioid and non-opioid properties. Acetaminophen is a mild analgesic and antipyretic agent which can cause centrilobular hepatic necrosis in toxic doses. On the other hand, alcohol causes death from the hepatic disease. Alcoholic liver disease (ALD) such as alcoholic fatty liver, alcoholic hepatitis, and alcoholic fibrosis is the most common liver disease. Male rats were randomly assigned into three groups. The control group received normal saline, the group 2 receiving acetaminophen at the dose of 250 mg/kg/day and group 3 received ethanol at the beginning dose of 3 g/kg/day and slowly increased to 6 g/kg/day. Tramadol added to perfusion solution with the concentration of 500 ng/ml. Samples were collected during 180 minutes and analyte concentrations were determined by HPLC method. The concentration of tramadol and its three main metabolites O-desmethyltramadol (M1) and N-desmethyltramadol (M2) and N,O-didesmethyltramadol (M5) were determined in perfusate samples. An increase in the elimination half-life and reduced clearance rate of tramadol was seen in acetaminophen and ethanol groups in comparison to control group. Also, significant reductions in the AUC of metabolites of tramadol in acetaminophen and ethanol groups were seen as compared to control group.