Afecto cafeína y analgésicos en ratas

Original Paper
Pharmacology 2001;63:234–239
Received: April 5, 2001 Revised and accepted: April 11, 2001

Ketoprofen-Induced Cyclooxygenase Inhibition in Renal Medulla and Platelets of Rats Treated with Caffeine
Martin Sommerauer a Mehmet Ates b Hans Gühring b Kay Brune b Rainer Amann a Bernhard A. Peskar a
a Institute

of Experimental and Clinical Pharmacology, University of Graz,Austria and b Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Germany

Key Words Caffeine W Cyclooxygenase W Kidney W Ketoprofen W Real-time RT-PCR W Prostaglandin W Thromboxane

Abstract It has been suggested that caffeine can augment analgesic activity and aggravate side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of thepresent study was to investigate a possible interaction between ketoprofen and caffeine on prostaglandin (PG) biosynthesis and cyclooxygenase (COX) mRNA expression in the rat renal medulla ex vivo. Treatment of rats with ketoprofen (60 min before) resulted in a dosedependent (estimated ID50 0.3 mg/kg p.o.) reduction of PGE2 biosynthesis in renal medulla ex vivo. Ketoprofen (0.3 mg/kg)-inducedinhibition of PGE2 biosynthesis was stable between 30 and 180 min and still detectable 300 min after drug administration. Caffeine (10 mg/kg) did not cause a detectable effect on its own, nor did it significantly affect ketoprofen-induced inhibition of renal medullary PGE2 biosynthesis. Similar results were obtained with repeated daily drug administration for 1 week: there was no significant effect ofcaffeine on ketoprofen-induced inhibition of renal medullary PGE2 bio-

synthesis. The absence of significant caffeine effects on ketoprofen-induced inhibition of renal medullary PGE2 biosynthesis was paralleled by experiments showing no significant effect of caffeine on ketoprofen-induced inhibition of platelet thromboxane (TX)B2 biosynthesis. Additional experiments showed increased COX-2 mRNAexpression in the renal medulla 60 min after ketoprofen administration, that was not significantly influenced by concomitant caffeine treatment. Treatment of rats with ketoprofen for 1 week had no significant effects on COX2 mRNA expression. The present results show that ketoprofen caused inhibition of PGE2 biosynthesis in the rat renal medulla ex vivo with a potency similar to that reported forin vivo models suggesting that the ex vivo approach is a valid model to test a possible interference of caffeine with ketoprofen-induced COX inhibition. The absence of detectable effects of caffeine on time course or magnitude of ketoprofen-induced suppression of PGE2 biosynthesis in this model indicates, therefore, that possible adverse actions of co-administered caffeine on renal function are notrelated to interference with renal COX inhibition.
Copyright © 2001 S. Karger AG, Basel

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© 2001 S. Karger AG, Basel 0031–7012/01/0634–0234$17.50/0 Accessible online at: www.karger.com/journals/pha

Bernhard A. Peskar Department of Experimental and Clinical Pharmacology University of Graz, Universitätsplatz 4, A–8010 Graz(Austria) Tel. +43 316 380 4306, Fax +43 316 380 9645 E-Mail bernhard.peskar@kfunigraz.ac.at

Introduction

The relationship between non-phenacetin combined analgesic acids with caffeine and nephropathy is still controversially discussed [1–3]. Early findings suggest that caffeine increases the nephrotoxic potential of nonsteroidal anti-inflammatory drugs (NSAIDs) as well asphenacetin-containing and non-phenacetin mixtures [4, 5]. Most NSAIDs inhibit cyclooxygenases (COX-1, COX2), key enzymes in prostaglandin (PG) and thromboxane (TX) biosynthesis. The inhibition of COX is presumed to be mainly responsible for the anti-inflammatory effect of these drugs [6, 7] although additional sites of action, including CNS effects, may contribute to observed therapeutic effects [8, 9]. In...