Pharmacokinetic investigation of brain drug distribution in health and disease - a preliminary study of fraction unbound and Kp in wild type and transgenic animals
Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Introduction: The blood-brain barrier (BBB) is an important physical, metabolic and dynamic barrier that helps to maintain homeostasis and function of the brain. It consists of endothelia cells that constitute the walls of the brain capillaries and form a border between the central nervous system (CNS) and the blood. Studies indicate that the BBB is affected in many disease conditions, both systemic and neurological. To study brain drug distribution in Parkinson’s disease (PD) and to detect potential changes at the BBB, drugs with different properties can be administered to wild type (WT) and transgenic animals, like the (Thy1)-h[A30P]αSYN mice(A30P mice). In order to reduce the number of animals, the drugs can be administered simultaneously as a cassette. In this study the cassette included levofloxacin, paliperidone, diazepam, digoxin and oxycodone. Aim: The aim of this project was to investigate possible differences in the unbound fraction of drug in brain (fu,brain) as well as the brain-to-plasma concentration ratio (Kp) between WT and A30P mice. To accomplish this, an aim was also to develop an LC-MS/MS method for the simultaneous analysis of the cassette compounds. Material and method: An LC-MS/MS method was developed for the compounds digoxin, diazepam, levofloxacin and paliperidone. Oxycodone was analyzed separately. Equilibrium dialysis was performed on A30P and WT specimens of right rostral and caudal brain regions. WT and A30P mice were subcutaneously administered with the cassette. Blood and right caudal brain samples were collected at three time points; 0.5, 1 and 3h, and further analyzed with LC-MS/MS. Result: A difference was observed in the fu,brain for digoxin, levofloxacin and paliperidone between the WT and A30P in the caudal brain region. The Kp did not differ for any of the compounds, indicating that there might be a difference also in BBB transport. A decrease in elimination rate in both plasma and brain was observed for paliperidone, diazepam, levofloxacin and oxycodone in A30P mice. Conclusion: The binding to brain tissue seems to differ between the WT and A30P mice in the caudal brain region for some compounds and the elimination rate seems to be affected in the A30P mice. The Kp does not seem to differ between healthy and diseased animals for any of the compounds included in the cassette. Further studies are needed, with additional drugs, in order to confirm the results.
Place, publisher, year, edition, pages
2013. , 31 p.
IdentifiersURN: urn:nbn:se:uu:diva-204895OAI: oai:DiVA.org:uu-204895DiVA: diva2:641364
Subject / course
Master of Science Programme in Pharmacy
Hammarlund-Udenaes, Margareta, ProfessorGustafsson, Sofia
Bengtsson, Jörgen, PhD