Dose- and time dependency and P-gp effects on brain distribution of antidepressants in vivo
Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Introduction: The novel antidepressant drug Compound A showed, in a pilot study at H. Lundbeck A/S, a dose dependent decrease in Kp,uu when administered continuously for three days in rats, whereas a constant Kp,uu profile was observed independent of dose when the drug was dosed acutely and examined after 30 minutes.
Aim: The aim of this study was to increase the knowledge of the Compound A characteristics, enabling optimization of drug usage, by investigating the dose- and time dependency on brain distribution for Compound A. Further the drug’s effect on P-gp was to be assessed.
Materials and Methods: The study was performed in vivo using both mice and rats. Compound-A and duloxetine (comparator drug) was administered via acute subcutaneous (S.C.) treatments, continuous treatments using subcutaneously implanted osmotic minipumps for 24 hours or 3 days and through repeated S.C. treatments over 3 days. Plasma and brain samples were collected in all experiments and were analyzed with LC-MS/MS.
Results and Conclusion: No dose dependency in Kp,uu was found in mice after continuous treatment with minipumps. The acute S.C. treatment with Compound A showed a nonproportional increase in Kp,uu when exceeding a dose of 0.3 mg/kg (~330 ng/ml) suggesting a possible saturation of P-gp. Time dependency was significant in rats but not in mice. A significant difference was discovered between Kp,uu in P-gp KO and WT rats (KO/WT ratio 1.9-2.5) and a trend like difference was found between P-gp MU and WT mice (MU/WT ratio 1.3-1.7) indicating that Compound A is a weak substrate for P-gp. The Kp,uu profile over increasing dose and time was similar for both P-gp MU/KO and WT groups indicating that no P-gp induction was involved.
Place, publisher, year, edition, pages
2014. , 44 p.
IdentifiersURN: urn:nbn:se:uu:diva-231578OAI: oai:DiVA.org:uu-231578DiVA: diva2:744973
H. Lundbeck A/S
Subject / course
Master of Science Programme in Pharmacy