Nov 21, 2014 - 129K7017), B-nicotinamide adenine dinucleotide phosphate hydrate (NADPH) (lot No: ...... Stern ST, Bruno MK, Hennig GE, Horton RA, Roberts JC, Cohen. SD. 2005. ... Jensen LS, Valentine J, Milne RW, Evans AM. 2004.
RESEARCH ARTICLE – Pharmacokinetics, Pharmacodynamics and Drug Transport and Metabolism
Glucosamine Enhances Paracetamol Bioavailability by Reducing Its Metabolism NIDAL A. QINNA,1 MARYAM H. SHUBBAR,1 KHALID Z. MATALKA,1 NAWZAT AL-JBOUR,2 MOHAMMAD A. GHATTAS,3 ADNAN A. BADWAN2 1
Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan The Jordanian Pharmaceutical Manufacturing Company PLC (JPM), Naor, Jordan 3 College of Pharmacy, Al Ain University of Science and Technology, Al Ain, United Arab Emirates 2
Received 7 May 2014; revised 17 September 2014; accepted 28 October 2014 Published online 21 November 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24269 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 I and phase I/II 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 C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:257–265, 2015 high doses of paracetamol. Keywords: glucosamine; paracetamol; bioavailability; metabolism; liver toxicity; pharmacokinetics; CYP enzymes
INTRODUCTION Paracetamol is the most common analgesic and antipyretic drug in the world. The therapeutic dose undergoes a heavy metabolism (80%–90%) by the liver in a short period of time and therefore lowers its bioavailability (BA).1 In humans, paracetamol is metabolized in the liver mainly by glucuronide conjugation (40%–50%) and sulfate conjugation (30%–40%), whereas a lesser portion (
