Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.
continuously measured and frequent blood samples were taken to determine the pharmacokinetics of the drugs. 3 CPT had no influence on the pharmacokinetics of CPA and the baseline values of the haemodynamic variables. Furthermore, no clear antagonism by CPT was observed of the CPA-induced reduction in mean arterial pressure. However, CPT antagonized the effect on heart rate, and with increasing CPT concentrations, a parallel shift of the CPA concentration-effect relationship to the right was observed. 4 An agonist-antagonist interaction model was used to characterize the interaction quantitatively. On the basis of this model, the pharmacodynamic parameters of both CPA and CPT could be estimated.For CPA the values were (mean s.e.): E. = 198 ± 11 b.p.m., ECm = 2.1 ± 0.7 ng ml-', Hill factor = 2.3 ± 0.6 and for CPT: ECm = 3.7 ± 0.3 ng ml-and Hill factor = 3.1 ± 0.1.
The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.
1 The purpose of this study was to develop and validate an integrated pharmacokineticpharmacodynamic model for the anti-lipolytic e ects of the adenosine A 1 -receptor agonist N 6 -(psulphophenyl)adenosine (SPA). Tissue selectivity of SPA was investigated by quanti®cation of haemodynamic and anti-lipolytic e ects 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-esteri®ed fatty acid (NEFA) and b-hydroxybutyrate levels. Blood pressure and heart rate were monitored continuously. 3 The relationship between the SPA concentrations and the NEFA lowering e ect was described by the indirect suppression model. Administration of SPA at di erent rates and doses (60 mg kg 71 in 5 min and 15 min, and 120 mg kg 71 in 60 min) led to uniform pharmacodynamic parameter estimates. The averaged parameters (mean+s.e., n=19) were E max : 780+2% (% change from baseline), EC 50 : 22+2 ng ml 71 , and Hill factor: 2.2+0.2. 4 In another group, given 400 mg kg 71 SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipolytic e ect were derived within the same animal. The reduction in heart rate was directly related to blood concentration on the basis of the sigmoidal E max model. SPA inhibited lipolysis at concentrations lower than those required for an e ect on heart rate. The EC 50 values (mean+s.e., n=6) were 131+31 ng ml 71 and 20+3 ng ml 71 for heart rate and NEFA lowering e ect, respectively. 5 In conclusion, the relationship between blood SPA concentrations and anti-lipolytic e ect was adequately described by the indirect suppression model. For SPA a 6 fold di erence in potency was observed between the e ects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.
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