title: Quantitative pharmacokinetic-pharmacodynamic modelling of baclofen-mediated cardiovascular effects using BP and heart rate in rats.
abstract: While the molecular pathways of baclofen toxicity are understood, the relationships between baclofen-mediated perturbation of individual target organs and systems involved in cardiovascular regulation are not clear. Our aim was to use an integrative approach to measure multiple cardiovascular-relevant parameters [CV: mean arterial pressure (MAP), systolic BP, diastolic BP, pulse pressure, heart rate (HR); CNS: EEG; renal: chemistries and biomarkers of injury] in tandem with the pharmacokinetic properties of baclofen to better elucidate the site(s) of baclofen activity.
  
  
  
  Han-Wistar rats were administered vehicle or ascending doses of baclofen (3, 10 and 30 mg·kg(-1) , p.o.) at 4 h intervals and baclofen-mediated changes in parameters recorded. A pharmacokinetic-pharmacodynamic model was then built by implementing an existing mathematical model of BP in rats.
  
  
  
  Final model fits resulted in reasonable parameter estimates and showed that the drug acts on multiple homeostatic processes. In addition, the models testing a single effect on HR, total peripheral resistance or stroke volume alone did not describe the data. A final population model was constructed describing the magnitude and direction of the changes in MAP and HR.
  
  
  
  The systems pharmacology model developed fits baclofen-mediated changes in MAP and HR well. The findings correlate with known mechanisms of baclofen pharmacology and suggest that similar models using limited parameter sets may be useful to predict the cardiovascular effects of other pharmacologically active substances.
authors.affiliation: Drug Safety and Metabolism, AstraZeneca-US, Waltham, MA, USA.
authors.forename: Harriet
authors.initials: H
authors.lastname: Kamendi
authors.affiliation: Drug Safety and Metabolism, AstraZeneca-US, Waltham, MA, USA.
authors.forename: Herbert
authors.initials: H
authors.lastname: Barthlow
authors.affiliation: Drug Safety and Metabolism, AstraZeneca-US, Waltham, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lengel
authors.affiliation: Analytical Group, Cancer Chemistry, AstraZeneca-US, Waltham, MA, USA.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Beaudoin
authors.affiliation: Drug Safety and Metabolism, AstraZeneca-US, Waltham, MA, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Snow
authors.affiliation: Drug Safety and Metabolism, AstraZeneca-US, Waltham, MA, USA. jay.mettetal@astrazeneca.com.
authors.forename: Jerome T
authors.initials: JT
authors.lastname: Mettetal
authors.affiliation: Drug Safety and Metabolism, AstraZeneca-US, Waltham, MA, USA. russell.bialecki@dupont.com.
authors.forename: Russell A
authors.identifier: 0000-0002-6215-1440
authors.initials: RA
authors.lastname: Bialecki
mesh_terms: D000818:Animals; D001418:Baclofen / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001418:Baclofen