期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 153, 期 1, 页码 164-174出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjp.0707539
关键词
tesofensine; NS2330; active metabolite; potency; pharmacokinetic/pharmacodynamic modelling; Alzheimer's disease; Parkinson's disease; obesity; CNS; WIN35,428
Background and purpose: Tesofensine is a centrally acting drug under clinical development for Alzheimer's disease, Parkinson's disease and obesity. In vitro, the major metabolite of tesofensine (M1) displayed a slightly higher activity, which however has not been determined in vivo. The aims of this investigation were (i) to simultaneously accomplish a thorough characterization of the pharmacokinetic (PK) properties of tesofensine and M1 in mice and (ii) to evaluate the potency ( pharmacodynamics, PD) and concentration-time course of the active metabolite M1 relative to tesofensine and their impact in vivo using the PK/PD modelling approach. Experimental approach: Parent compound, metabolite and vehicle were separately administered intravenously and orally over a wide dose range (0.3-20mgkg(-1)) to 228 mice. Concentrations of tesofensine and M1 were measured; inhibition of the dopamine transporter was determined by co-administration of [H-3]WIN35,428 as the pharmacodynamic measure. Key results: Pharmacokinetics of tesofensine and M1 were best described by one-compartment models for both compounds. Nonlinear elimination and metabolism kinetics were observed with increasing dose. The PK/PD relationship was described by an extended E-max model. Effect compartments were used to resolve observed hysteresis. EC50 values of M1, as an inhibitor of the dopamine transporter, were 4-5-fold higher than those for tesofensine in mice. Conclusions and implications: The lower potency of M1 together with similar to 8-fold higher trough steady-state concentrations suggest that M1 did contribute to the overall activity of tesofensine in mice.
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