Abstract
In this study, we analyzed the antilipolytic effects of sixN6-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). AllN6-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 (α, 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.
Footnotes
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Send reprint requests to: Piet H. Van der Graaf, Ph.D., Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, P.O. Box 9503, 2300RA Leiden, The Netherlands. E-mail:vdgraaf{at}lacdr.leidenuniv.nl
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↵1 This work was supported by the Academy Fellowship Program of the Royal Netherlands Academy of Arts and Sciences (P.H. Van der G.).
- Abbreviations:
- CPA
- N6-cyclopentyladenosine
- dCPA
- deoxy-N6-cyclopentyladenosine
- 8MCPA
- 8-(methylamino)-N6-cyclopentyladenosine
- 8ECPA
- 8-(ethylamino)-N6-cyclopentyladenosine
- 8BCPA
- 8-(butylamino)-N6-cyclopentyladenosine
- NEFA
- nonesterified fatty acid
- Cl
- clearance
- VdSS
- volume of distribution at steady state
- Em
- maximum effect
- Received December 31, 1998.
- Accepted April 2, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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