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Hanadi Adi Alshaker

Glucosamine Effect on Propranolol Bioavailability
Hanadi Adi Alshaker
A Thesis Submitted in Partial Fulfillment of the Requirements for the
Degree of
Master of Science
in Pharmaceutical Sciences
University of Petra
June 2015
 Dr. Nidal Qinna
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
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.
First and foremost, I am thankful to his Almighty ALLAH’s help to complete my
thesis. It is a genuine pleasure to express my deep thanks to those who contributed to my
thesis. I would like to express my deepest reverence to my advisor Dr. Nidal Qinna for his
enthusiasm, valuable advice, immense knowledge, support, directions, and suggestions he
provided me with. My sincere thanks go to Prof. Nasir Idkaidek for his logical way of
thinking, his input and perspective which were of great value for this thesis. My thanks also
go to Dr. Adnan Badwan and to everybody working at the Jordanian Pharmaceutical
Manufacturing Company (JPM). My thanks also go to the examination committee for their
valuable suggestions. I also would like to thank Mr. Mujtaba Badr and Hamza Al-Hroub for
their assistance and help. Special thanks are owed to Mohammad Albayed’s fine technical
assistance, his invaluable help, and cooperation at the animal house. I am also grateful to
my friend Mrs. Nehal Jaber for her friendly helpful attitude, cheerful and constant support
and to my friend Ala’ Murrar for her nice words.
Lastly but not least, I would like to thank my family. I cannot find words to express
my gratitude toward the most special woman in my heart now and forever, for my mother
who made it possible for me by her support, prayers, and special care. I owe a special debt
of gratitude to my sister Dr. Heba, my father who encouraged me through this thesis and to
my brothers for their infinite encouragement. I thank them all because they have believed
in my ability and supported me throughout my study.