| 14718609 |
Zuideveld KP, Van der Graaf PH, Newgreen D, Thurlow R, Petty N, Jordan P, Peletier LA, Danhof M: Mechanism-based pharmacokinetic-pharmacodynamic modeling of 5-HT1A receptor agonists: estimation of in vivo affinity and intrinsic efficacy on body temperature in rats. J Pharmacol Exp Ther. 2004 Mar;308(3):1012-20. Epub 2004 Jan 8.
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-cyclohexanec arboxamide] and of the log tau ranging from -1.27 for WAY-100,135 [N-(1,1-dimethylethyl)-4-(2-methoxyphenyl)-alpha-phenyl-1-piperazine-propa namide] 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. |
35(0,1,1,5) |