Pharmacokinetic changes of tramadol in rats with hepatotoxicity induced by ethanol and acetaminophen in perfused rat liver model

• Published in: Alcohol (Fayetteville, N.Y.) N.Y.), 2019-06, Vol.77, p.49-57
• Main Authors: Mohammadi, Saeid, Nezami, Alireza, Esmaeili, Zohre, Rouini, Mohammad Reza, Ardakani, Yalda H., Lavasani, Hoda, Hassanzadeh, Gholamreza, Ghazi-Khansari, Mahmoud
• Format: Article
• Language: English
• Subjects: Acetaminophen; Acetaminophen - adverse effects; Acetaminophen - pharmacokinetics; Alcohol; Alcohol use; Alcoholic beverages; Analgesics; Analgesics, Non-Narcotic - adverse effects; Analgesics, Non-Narcotic - pharmacokinetics; Analgesics, Opioid - adverse effects; Analgesics, Opioid - pharmacokinetics; Animal models; Animals; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Convulsions & seizures; Cytochrome; Drug dosages; Enzymatic activity; Enzymes; Ethanol; Ethanol - adverse effects; Ethanol - pharmacokinetics; Fatty liver; FDA approval; Fibrosis; Hepatitis; Hepatotoxicity; High performance liquid chromatography; HPLC; Laboratories; Liquid chromatography; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver diseases; Liver perfusion; Male; Metabolism; Metabolites; Narcotics; Opioids; Oxidative stress; Pain; Perfusion; Perfusion - methods; Pharmacokinetics; Prescription drugs; Random Allocation; Rats; Rats, Sprague-Dawley; Rodents; Tramadol; Tramadol - adverse effects; Tramadol - pharmacokinetics; Urine
• ISSN: 0741-8329; 1873-6823
• DOI: 10.1016/j.alcohol.2018.09.006

Tramadol is an opioid agonist with activation monoaminergic properties. It can be administered orally, rectally, intravenously, or intramuscularly as a centrally acting analgesic. Liver injury can lead to changes in the metabolism of tramadol. In this study, the rate of tramadol metabolism in rats with damaged liver induced by ethanol and acetaminophen was assessed in a recirculation perfusion system. Acetaminophen is a mild analgesic and antipyretic agent, which can cause centrilobular hepatic necrosis in toxic doses, whereas alcohol causes death due to liver diseases. Alcoholic liver disease (ALD), such as alcoholic fatty liver, alcoholic hepatitis, and alcoholic fibrosis, is the most common liver disease. The aim of this study was to investigate the alteration in tramadol metabolism in different hepatotoxicity conditions in animal models. Male rats were randomly assigned to three groups. The control group received normal saline, group 2 received acetaminophen at the dose of 250 mg/kg/day, and group 3 received ethanol at the beginning dose of 3 g/kg/day, which was slowly increased to 6 g/kg/day. Tramadol was added to the perfusion solution at the concentration of 500 ng/mL. Samples were collected during 180 min, and analyte concentrations were determined by the High-Performance Liquid Chromatography (HPLC) method. The concentration of tramadol and its three main metabolites, O-desmethyltramadol (M1), N-desmethyltramadol (M2), and N,O-didesmethyltramadol (M5), were determined in perfusate samples. Ethanol and acetaminophen significantly affected the pattern of weight gain and liver weights before perfusion and caused a significant increase in enzyme activities. Moreover, histopathologic examination revealed that ethanol and acetaminophen caused liver damage. An increase in the elimination half-life and reduced clearance rate of tramadol were seen in the acetaminophen and ethanol groups, in comparison to the control group. Additionally, significant reductions in the Area Under the Curve (AUC) of metabolites of tramadol (M1, M2, and M5) were observed in the acetaminophen and ethanol groups in the perfused rat liver model. Liver damage caused by ethanol and acetaminophen during 45 days in animals leads to a significant reduction in the level of tramadol metabolites. Therefore, in patients with liver damage caused by ethanol and acetaminophen, caution needs to be considered when prescribing tramadol. [Display omitted] •Ethanol and acetaminophen significantly