title: Influence of plasma protein binding on pharmacodynamics: Estimation of in vivo receptor affinities of beta blockers using a new mechanism-based PK-PD modelling approach.
abstract: 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 beta 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(-)-atenolol, S(-)-propranolol, S(-)-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(-)-propranolol (ratio K(B,vivo)/K(B,vitro) approximately 6.8). For the free drug, the correlation approximated the line of identity. Using this model, for beta-blockers the free plasma concentration appears to be the best predictor of in vivo pharmacodynamics.
authors.affiliation: Division of Pharmacology, Leiden-Amsterdam Center for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands.
authors.forename: T J
authors.initials: TJ
authors.lastname: van Steeg
authors.forename: V B
authors.initials: VB
authors.lastname: Boralli
authors.forename: E H J
authors.initials: EH
authors.lastname: Krekels
authors.forename: P
authors.initials: P
authors.lastname: Slijkerman
authors.forename: J
authors.initials: J
authors.lastname: Freijer
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.forename: E C M
authors.initials: EC
authors.lastname: de Lange
mesh_terms: D000318:Adrenergic beta-Agonists / Q000097:blood / Q000493:pharmacokinetics; D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008790:Metoprolol / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D008954:Models, Biological; D011433:Propranolol / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013999:Timolol / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D001798:Blood Proteins; D011943:Receptors, Adrenergic, beta; D013999:Timolol; D011433:Propranolol; D008790:Metoprolol; D007545:Isoproterenol