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Br J Pharmacol. 2008 Jan;153(1):164-74. Epub 2007 Nov 5.

Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach.

Author information

1
Department of Clinical Pharmacy, Freie Universitaet Berlin, Institute of Pharmacy, Berlin, Germany.

Abstract

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 (0.3-20 mg kg(-1)) to 228 mice. Concentrations of tesofensine and M1 were measured; inhibition of the dopamine transporter was determined by co-administration of [(3)H]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. EC(50) 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 approximately 8-fold higher through steady-state concentrations suggest that M1 did contribute to the overall activity of tesofensine in mice.

PMID:
17982477
PMCID:
PMC2199391
DOI:
10.1038/sj.bjp.0707539
[Indexed for MEDLINE]
Free PMC Article
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