title: Mechanism-based pharmacokinetic-pharmacodynamic modeling of 5-HT1A receptor agonists: estimation of in vivo affinity and intrinsic efficacy on body temperature in rats.
abstract: The pharmacokinetic-pharmacodynamic (PK-PD) correlations of seven prototypical 5-HT(1A) agonists were analyzed on the basis of a recently proposed semi-mechanistic PK-PD model for the effect on body temperature. The resulting concentration-effect relationships were subsequently analyzed on the basis of the operational model of agonism to estimate the operational affinity (pK(A)) and efficacy (log tau) at the 5-HT(1A) receptor in vivo. The values obtained in this manner were compared with estimates of the affinity (pK(i)) and intrinsic efficacy (log[agonist ratio]) in a receptor-binding assay. Between 5-HT(1A) agonists wide differences in in vivo affinity and efficacy were observed, with values of the pK(A) ranging from 5.67 for flesinoxan to 8.63 for WAY-100,635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridinyl-cyclohexanecarboxamide] and of the log tau ranging from -1.27 for WAY-100,135 [N-(1,1-dimethylethyl)-4-(2-methoxyphenyl)-alpha-phenyl-1-piperazine-propanamide] to 0.62 for R-(+)-8-hydroxy-2-[di-n-propylamino)tetralin. Poor correlations were observed between the in vivo receptor affinity (pK(A)) and the affinity estimates in the in vitro receptor binding assay (pK(i); r(2) = 0.55, P > 0.05), which could in part be explained by differences in blood-brain distribution. In contrast, a highly significant correlation was observed between the efficacy parameters in vivo (log tau) and in vitro (log [agonist ratio]; r(2) = 0.76, P < 0.05). Thus by combining the previously proposed semi-mechanistic PK-PD model for the effect on body temperature with the operational model of agonism, a full mechanistic PK-PD model for 5-HT(1A) receptor agonists has been obtained, which is highly predictive of the in vivo intrinsic efficacy.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratory, Leiden, The Netherlands.
authors.forename: Klaas P
authors.initials: KP
authors.lastname: Zuideveld
authors.forename: Piet H
authors.initials: PH
authors.lastname: Van der Graaf
authors.forename: Donald
authors.initials: D
authors.lastname: Newgreen
authors.forename: Richard
authors.initials: R
authors.lastname: Thurlow
authors.forename: Nicola
authors.initials: N
authors.lastname: Petty
authors.forename: Paul
authors.initials: P
authors.lastname: Jordan
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Peletier
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000818:Animals; D001665:Binding Sites; D001831:Body Temperature / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D051381:Rats; D017208:Rats, Wistar; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists