Abstract
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.
Footnotes
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DOI: 10.1124/jpet.103.059030.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine, serotonin; R-8-OH-DPAT, R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin; S-8-OH-DPAT, S-(+)-8-hydroxy-2-(di-n-propylamino)tetralin; PK-PD, pharmacokinetic-pharmacodynamic; 1-PP, 1-(2-pyrimidinyl)-piperazine; HPLC, high performance liquid chromatography; MS, mass spectrometry; SPA, scintillation proximity assay; NSB, nonspecific binding; DMSO, dimethyl sulfoxide; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; e.i.v., error-in-variables; α, upper asymptote of the concentration effect relationship; AIC, Akaike Information Criterion; ϵ, residual error; η, inter-individual variation; γ, amplification of the set point signal; SC50, concentration at 50% maximum stimulus; Smax, maximum stimulus the drug can produce; WAY-100,135, N-(1,1-dimethylethyl)-4-(2-methoxyphenyl)-α-phenyl-1-piperazinepropanamide; WAY-100,635, N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridinyl-cyclohexanecarboxamide.
- Received August 25, 2003.
- Accepted November 25, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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