PT  - JOURNAL ARTICLE
AU  - Klaas P. Zuideveld
AU  - Piet H. Van der Graaf
AU  - Donald Newgreen
AU  - Richard Thurlow
AU  - Nicola Petty
AU  - Paul Jordan
AU  - Lambertus A. Peletier
AU  - Meindert Danhof
TI  - Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of 5-HT<sub>1A</sub> Receptor Agonists: Estimation of in Vivo Affinity and Intrinsic Efficacy on Body Temperature in Rats
AID  - 10.1124/jpet.103.059030
DP  - 2004 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1012--1020
VI  - 308
IP  - 3
4099  - http://jpet.aspetjournals.org/content/308/3/1012.short
4100  - http://jpet.aspetjournals.org/content/308/3/1012.full
SO  - J Pharmacol Exp Ther2004 Mar 01; 308
AB  - The pharmacokinetic-pharmacodynamic (PK-PD) correlations of seven prototypical 5-HT1A 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 (pKA) and efficacy (log τ) at the 5-HT1A receptor in vivo. The values obtained in this manner were compared with estimates of the affinity (pKi) and intrinsic efficacy (log[agonist ratio]) in a receptor-binding assay. Between 5-HT1A agonists wide differences in in vivo affinity and efficacy were observed, with values of the pKA 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 τ ranging from –1.27 for WAY-100,135 [N-(1,1-dimethylethyl)-4-(2-methoxyphenyl)-α-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 (pKA) and the affinity estimates in the in vitro receptor binding assay (pKi; r2 = 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 τ) and in vitro (log [agonist ratio]; r2 = 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-HT1A receptor agonists has been obtained, which is highly predictive of the in vivo intrinsic efficacy. The American Society for Pharmacology and Experimental Therapeutics