title: Pharmacokinetic-pharmacodynamic modelling of the anti-lipolytic and anti-ketotic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine in rats.
abstract: 1. The purpose of this study was to develop and validate an integrated pharmacokinetic-pharmacodynamic model for the anti-lipolytic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine (SPA). Tissue selectivity of SPA was investigated by quantification of haemodynamic and anti-lipolytic effects in individual animals. 2. After intravenous infusion of SPA to conscious normotensive Wistar rats, arterial blood samples were drawn for determination of blood SPA concentrations, plasma non-esterified fatty acid (NEFA) and beta-hydroxybutyrate levels. Blood pressure and heart rate were monitored continuously. 3. The relationship between the SPA concentrations and the NEFA lowering effect was described by the indirect suppression model. Administration of SPA at different rates and doses (60 microg kg[-1] in 5 min and 15 min, and 120 microg kg[-1] in 60 min) led to uniform pharmacodynamic parameter estimates. The averaged parameters (mean+/-s.e., n=19) were Emax: -80+/-2% (% change from baseline), EC50: 22+/-2 ng ml(-1), and Hill factor: 2.2+/-0.2. 4. In another group, given 400 microg kg(-1) SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipolytic effect were derived within the same animal. The reduction in heart rate was directly related to blood concentration on the basis of the sigmoidal Emax model. SPA inhibited lipolysis at concentrations lower than those required for an effect on heart rate. The EC50 values (mean+/-s.e., n=6) were 131+/-31 ng ml(-1) and 20+/-3 ng ml(-1) for heart rate and NEFA lowering effect, respectively. 5. In conclusion, the relationship between blood SPA concentrations and anti-lipolytic effect was adequately described by the indirect suppression model. For SPA a 6 fold difference in potency was observed between the effects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.
authors.affiliation: Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
authors.forename: E A
authors.initials: EA
authors.lastname: van Schaick
authors.forename: H J
authors.initials: HJ
authors.lastname: de Greef
authors.forename: M W
authors.initials: MW
authors.lastname: Langemeijer
authors.forename: M J
authors.initials: MJ
authors.lastname: Sheehan
authors.forename: A P
authors.initials: AP
authors.lastname: IJzerman
authors.forename: M
authors.initials: M
authors.lastname: Danhof
mesh_terms: D020155:3-Hydroxybutyric Acid; D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D006885:Hydroxybutyrates / Q000097:blood; D000960:Hypolipidemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000187:drug effects
chemical_list: D001798:Blood Proteins; D005230:Fatty Acids, Nonesterified; D006885:Hydroxybutyrates; D000960:Hypolipidemic Agents; C109113:N(6)-(4-sulfophenyl)adenosine; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D000241:Adenosine; D020155:3-Hydroxybutyric Acid