title: Pharmacokinetic/pharmacodynamic modelling of the anti-hyperalgesic and anti-nociceptive effect of adenosine A1 receptor partial agonists in neuropathic pain.
abstract: The objective of this investigation was to characterise the pharmacokinetic-pharmacodynamic correlation of adenosine A1 receptor partial agonists in the chronic constriction injury model of neuropathic pain. Following intravenous administration of 8-methylamino-N6-cyclopentyl-adenosine (MCPA; 10 mg/kg) and 2'deoxyribose-N6-cyclopentyl-adenosine (2'dCPA; 20 mg/kg), the time course of the effect on the mechanical paw pressure threshold was determined in conjunction with plasma concentrations. Population pharmacokinetic/pharmacodynamic analysis was applied to derive individual concentration-effect relationships. A composite model consisting of an E(max) model for the anti-hyperalgesic effect in combination with a linear model for the anti-nociceptive effect accurately described the concentration-effect relationship. For both compounds, a full anti-hyperalgesic effect was observed. The values of the EC50 for the anti-hyperalgesic effect were (mean+/-S.D.): 3170+/-1460 and 2660+/-1200 ng/ml for MCPA and 2'dCPA versus 178+/-51 ng/ml for the reference full agonist 5'deoxyribose-N6-cyclopentyl-adenosine (5'dCPA). The values of the slope for the anti-nociceptive effect were 1.9+/-0.30 and 1.2+/-0.20 g.microl/ng, respectively, versus 55+/-8 g microl/ng for 5'dCPA. Adenosine A1 receptor partial agonists behave as full agonists with regard to the anti-hyperalgesic effect in neuropathic pain, but the anti-nociceptive effect is diminished.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratory, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
authors.forename: Marloes P
authors.initials: MP
authors.lastname: Schaddelee
authors.forename: Sue D
authors.initials: SD
authors.lastname: Collins
authors.forename: Joost
authors.initials: J
authors.lastname: DeJongh
authors.forename: Albertus G
authors.initials: AG
authors.lastname: de Boer
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D000465:Algorithms; D000700:Analgesics / Q000493:pharmacokinetics* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003839:Deoxyadenosines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006930:Hyperalgesia / Q000517:prevention & control*; D007275:Injections, Intravenous; D008297:Male; D009437:Neuralgia / Q000517:prevention & control*; D051381:Rats; D013997:Time Factors
chemical_list: C495036:2'-deoxyribose-N6-cyclopentyladenosine; C495035:8-methylamino-N6-cyclopentyladenosine; D058907:Adenosine A1 Receptor Agonists; D000700:Analgesics; D003839:Deoxyadenosines; D000241:Adenosine