title: Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Clinical Pharmacy, Freie Universitaet Berlin, Institute of Pharmacy, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Lehr
authors.forename: A
authors.initials: A
authors.lastname: Staab
authors.forename: C
authors.initials: C
authors.lastname: Tillmann
authors.forename: E Ø
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: D
authors.initials: D
authors.lastname: Trommeshauser
authors.forename: H G
authors.initials: HG
authors.lastname: Schaefer
authors.forename: C
authors.initials: C
authors.lastname: Kloft
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism* / Q000494:pharmacology*; D002491:Central Nervous System Agents / Q000494:pharmacology*; D003198:Computer Simulation; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008954:Models, Biological
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002491:Central Nervous System Agents; D050483:Dopamine Plasma Membrane Transport Proteins; C518479:Tesofensine