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Hanadi Adi Alshaker

Glucosamine Effect on Propranolol Bioavailability
by
Hanadi Adi Alshaker
A Thesis Submitted in Partial Fulfillment of the Requirements for the
Degree of
Master of Science
in Pharmaceutical Sciences
at
University of Petra
Amman-Jordan
June 2015
Supervisor
 Dr. Nidal Qinna
 
iii
Abstract
Propranolol (PRN) undergoes extensive first-pass metabolism by the liver resulting in a relatively low bioavailability (BA). Thus, multiple doses are required to achieve therapeutic effect, which causes increased side effects. Glucosamine (GlcN) is an amino monosaccharide that is used to treat osteoarthritis (OA) and rheumatoid arthritis (RA) in elderly patients due to its ability to maintain connective and cartilage tissues strength and flexibility. Therefore, this research aimed to study the effect of GlcN on PRN BA, as a possible event of drug-drug interaction that may occur in patients especially elderly patients receiving both drugs. As a result, this could help to recommend whether PRN dose adjustment should be necessary with GlcN administration. Initially, in order to investigate such drug interaction a validated HPLC method of PRN in rat serum and Krebs buffer was developed and validated. Later, in vivo experiments were carried out to determine the effect of GlcN on PRN. PRN area under curve (AUC) and maximum concentration (Cmax) were significantly decreased by 43% (p<0.01) and 34% (p<0.05), respectively for the highest GlcN dose 200 mg/kg. On the other hand, 100 mg/kg of GlcN did not change PRN AUC and Cmax (p>0.05). Additionally, 200 mg/kg of GlcN decreased intestinal permeability (Peff) and increased PRN clearance by 50%. Rifampin is an enzyme inducer which potently induces many CYP450, whereas cimetidine is an enzyme inhibitor that effectively reduces the metabolism of concomitant drugs. Therefore, it is used as a control in many of literature studies documenting its role in drug interactions. The results showed that rifampin, at 9 mg/kg did not change PRN AUC and Cmax (p>0.05), whereas 5 mg/kg of cimetidine increased PRN Cmax significantly by 86% (p<0.01) and AUC by 20% (p>0.05). However, in iv the in situ single pass intestinal perfusion (SPIP) experiments, GlcN increased PRN BA significantly (p<0.05) by two-fold at 60 min as compared to cimetidine and rifampin. This was confirmed by everted gut experiment where GlcN enhanced the absorption of PRN at 20, 40, and 60 min. Finally, using isolated hepatocyte cell culture, GlcN at 200 mM decreased PRN metabolism and increased PRN concentration significantly (p<0.05). On the other hand, 50 μM of rifampin increased PRN metabolism and decreased PRN concentration, whereas cimetidine at 5 μM increased PRN concentration as expected for such positive controls. Overall, GlcN decreased PRN BA in a dose-dependent manner by decreasing its in vivo intestinal absorption and permeability but increased PRN concentration levels in situ and in vitro. This might be attributed to factors prior intestinal absorption such as the pH of the stomach, PRN and GlcN pKa and the efflux transporter P-glycoprotein (P-gp). Furthermore, only the highest tested dose of GlcN (200 mM) was capable of affecting PRN levels when incubated with viable rat hepatocytes. Therefore, it might be necessary to prescribe PRN with GlcN with caution due to the current reported interactions. A dosage regimen adjustment of PRN might be required to achieve the desired therapeutic effect in patients receiving GlcN.