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Dose- and time dependency and P-gp effects on brain distribution of antidepressants in vivo
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2014 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

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.
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-231578OAI: oai:DiVA.org:uu-231578DiVA: diva2:744973
External cooperation
H. Lundbeck A/S
Subject / course
Educational program
Master of Science Programme in Pharmacy
Available from: 2014-09-09 Created: 2014-09-09 Last updated: 2014-09-09Bibliographically approved

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