title: Glucosamine enhances paracetamol bioavailability by reducing its metabolism.
abstract: Paracetamol has an extensive first-pass metabolism that highly affects its bioavailability (BA); thus, dose may be repeated several times a day in order to have longer efficacy. However, hepatotoxicity may arise because of paracetamol metabolism. Therefore, this project aimed to increase paracetamol BA in rats by glucosamine (GlcN). At GlcN-paracetamol racemic mixture ratio of 4:1 and paracetamol dose of 10 mg/kg, paracetamol area under the curve (AUC) and maximum concentration (Cmax ) were significantly increased by 99% and 66%, respectively (p < 0.05). Furthermore, paracetamol AUC and Cmax levels were increased by 165% and 88% in rats prefed with GlcN for 2 days (p < 0.001). Moreover, GlcN significantly reduced phase Ι and phase I/ΙΙ metabolic reactions in liver homogenate by 48% and 54%, respectively. Furthermore, GlcN molecule was found to possess a good in silico binding mode into the CYP2E1 active site-forming bidentate hydrogen bonding with the Thr303 side chain. Finally, serum ALT and AST levels of rats-administered high doses of paracetamol were significantly reduced when rats were prefed with GlcN (p < 0.01). In conclusion, GlcN can increase the relative BA of paracetamol through reducing its metabolism. This phenomenon is associated with reduction in hepatocytes injury following ingestion of high doses of paracetamol.
authors.affiliation: Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan.
authors.forename: Nidal A
authors.initials: NA
authors.lastname: Qinna
authors.forename: Maryam H
authors.initials: MH
authors.lastname: Shubbar
authors.forename: Khalid Z
authors.initials: KZ
authors.lastname: Matalka
authors.forename: Nawzat
authors.initials: N
authors.lastname: Al-Jbour
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghattas
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Badwan
mesh_terms: D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000506:poisoning; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000506:poisoning; D000818:Animals; D058633:Antipyretics / Q000037:antagonists & inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000506:poisoning; D001682:Biological Availability; D001711:Biotransformation; D002236:Carbohydrate Conformation; D020134:Catalytic Domain; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism / Q000517:prevention & control; D019392:Cytochrome P-450 CYP2E1 / Q000737:chemistry / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D030562:Databases, Protein; D019587:Dietary Supplements; D005260:Female; D018565:Food-Drug Interactions; D005944:Glucosamine / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D017207:Rats, Sprague-Dawley
chemical_list: D018712:Analgesics, Non-Narcotic; D058633:Antipyretics; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D008024:Ligands; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D005944:Glucosamine
keywords: CYP enzymes; bioavailability; glucosamine; liver toxicity; metabolism; paracetamol; pharmacokinetics