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Vol. 290, Issue 2, 702-709, August 1999
Divisions of Pharmacology (P.H. Van der G., E.A. Van S. S.A.G.V., H.J.M.M. De G., M.D.) and Medicinal Chemistry (A.P.IJ.),
Leiden/Amsterdam Center for Drug Research, Leiden, the Netherlands
In this study, we analyzed the antilipolytic effects of six
N6-cyclopentyladenosine analogs in rats and
developed a mechanistic pharmacokinetic-pharmacodynamic model to
quantify and predict the tissue-selective action of adenosine
A1 receptor agonists in vivo. Freely moving rats received
an i.v. infusion of vehicle or compound over 15 min. Arterial blood
samples were taken at regular time intervals for the determination of
concentrations of drugs using HPLC analysis and of nonesterified fatty
acids (NEFAs). All
N6-cyclopentyladenosine analogs that
were investigated produced a significant decrease in the NEFA plasma
concentration after i.v. infusion. The pharmacokinetic behavior of each
ligand was described by a standard two-compartment model. The
pharmacokinetic parameter estimates then were used to simultaneously
fit the individual (n = 6-8) time-NEFA
concentration profiles for each agonist to a physiological indirect
response model in combination with the Hill equation to obtain
estimates of the NEFA elimination rate constant
(ke) and upper asymptote (fractional
inhibition), midpoint location, and midpoint slope parameter (
,
pEC50, and nH, respectively) of
the concentration-effect relationship. Subsequently, the data were
analyzed with the operational model of agonism to obtain estimates of
in vivo affinity and efficacy. It was estimated that the in vivo
density and/or coupling of adenosine A1 receptors mediating
antilipolytic effects is ~38 times higher compared with the receptors
mediating bradycardia. The model predicts that it is possible to design
ligands that produce significant inhibition of lipolysis and are
completely devoid of cardiovascular effects in vivo.
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