Influence of plasma protein binding on pharmacodynamics: Estimation of in vivo receptor affinities of β blockers using a new mechanism-based PK–PD modelling approach
✍ Scribed by T.J. van Steeg; V.B. Boralli; E.H.J. Krekels; P. Slijkerman; J. Freijer; M. Danhof; E.C.M. de Lange
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 205 KB
- Volume
- 98
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
The objective of this investigation was to examine in a systematic manner the influence of plasma protein binding on in vivo pharmacodynamics. Comparative pharmacokinetic-pharmacodynamic studies with four b blockers were performed in conscious rats, using heart rate under isoprenaline-induced tachycardia as a pharmacodynamic endpoint. A recently proposed mechanism-based agonist-antagonist interaction model was used to obtain in vivo estimates of receptor affinities (K B,vivo ). These values were compared with in vitro affinities (K B,vitro ) on the basis of both total and free drug concentrations. For the total drug concentrations, the K B,vivo estimates were 26, 13, 6.5 and 0.89 nM for S(À)-atenolol, S(À)-propranolol, S(À)-metoprolol and timolol. The K B,vivo estimates on the basis of the free concentrations were 25, 2.0, 5.2 and 0.56 nM, respectively. The K B,vivo -K B,vitro correlation for total drug concentrations clearly deviated from the line of identity, especially for the most highly bound drug S(À)propranolol (ratio K B,vivo /K B,vitro $6.8). For the free drug, the correlation approximated the line of identity. Using this model, for b-blockers the free plasma concentration appears to be the best predictor of in vivo pharmacodynamics.