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Thromb Haemost 1996; 76(04): 592-597
DOI: 10.1055/s-0038-1650627
Original Article
Schattauer GmbH Stuttgart

The Effects on Platelet Aggregation and Prostanoid Biosynthesis of two Parenteral Analgesics: Ketorolac Tromethamine and Dipyrone

G geisslinger
The Department of Experimental and Clinical Pharmacology, Isreal
,
B A Peskar
1   The Department of Experimental and Clinical Pharmacology; University of Graz, Austria
,
D Pallapies
2   Department of Pharmacology and Toxicology, Ruhr-University, Bochum, Germany
,
R Sittl
3   Department of Anesthesiology, University of Erlangen, Erlangen, Germany
,
M Levy
4   Division of Medicine, Hadassah University Hospital, Jerusalem, Israel
,
K Brune
The Department of Experimental and Clinical Pharmacology, Isreal
› Author Affiliations
Further Information

Publication History

Received: 14 March 1996

Accepted after resubmission04 June 1996

Publication Date:
10 July 2018 (online)

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Summary

The pharmacokinetics and effects on platelet function of dipyrone (1.0 g; 2.5 g; i. v.) and ketorolac tromethamine (30 mg; i.m.) were studied in a three-way crossover study in twelve healthy subjects. The biosynthesis of thromboxane A2 in clotting whole blood ex vivo as well as collagen-induced platelet aggregation were determined before and up to 48 h after administration. Both prostanoid biosynthesis and platelet aggregation were inhibited by ketorolac tromethamine for a significantly longer period of time than by both doses of dipyrone. The changes in platelet functions correlated well with the serum concentrations of ketorolac or 4-methylaminoantipyrine and 4-aminoantipyrine. Using the sigmoidal Emax model the mean serum concentration (SD) of ketorolac, 4-methylaminoantipyrine and 4-aminoantipyrine inhibiting platelet TXB2 generation by 50% (EC50) in vitro was found to be 0.088 ± 0.031, 1.2 ± 0.3 and 10.2 ± 3.4 µg ml-1, respectively. In conclusion the recovery of platelet function after dipyrone administration is faster as compared to ketorolac tromethamine. This is in line with clinical observations and may be an advantage when these drugs are given as postoperative analgesics at the doses tested.

 

  • References

  • 1 Brune K, Alpermann H. Nonacidic pyrazoles: inhibition of prostaglandin production, carrageenan edema and yeast fever. Agents Actions 1983; 13: 360-363
    CrossrefPubMedGoogle Scholar
  • 2 Lai A, Pandey K, Chandra P, Pande SB. Dipyrone for treatment of postoperative pain. Anaesthesia 1973; 28: 43-47
    CrossrefPubMedGoogle Scholar
  • 3 Rook WH, Tomolonis AJ, Maloney PJ, Wallach MB, Schuler ME. The analgesic and anti-inflammatory profile of (°)-5-benzoyl-l,2-dihydro-3H-pyrrolo[l,2a]pyrrole-l-carboxylic acid (RS-37619). Agents Actions 1982; 12: 684-690
    CrossrefPubMedGoogle Scholar
  • 4 Guzman A, Yuste F, Toscano RA, Young JM, van Horn AR, Muchowski JM. Absolute configuration of (-)-5-benzoyl-1,2-dihydro-3H-pyrro-lo[l,2a]pyrrole-l-carboxylic acid, the active enantiomer of ketorolac. J MedChem 1986; 29: 589-591
    PubMedGoogle Scholar
  • 5 Levy M, Zylber-Katz E, Rosenkranz B. Clinical pharmacokinetics of dipyrone and its metabolites. Clin Pharmacokinet 1995; 28: 216-234
    CrossrefPubMedGoogle Scholar
  • 6 Levy M, Flusser D, Zylber-Katz E, Granit L. Plasma kinetics of dipyrone metabolites in rapid and slow acetylators. Eur J Clin Pharmacol 1984; 27: 453-458
    CrossrefPubMedGoogle Scholar
  • 7 Buckley MMT, Brogden RN. Ketorolac: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1990; 39: 86-109
    CrossrefPubMedGoogle Scholar
  • 8 Hayball PJ, Wrobel J, Tamblyn JG, Nation RL. The pharmacokinetics of ketorolac enantiomers following intramuscular administration of the race-mate. Br J Clin Pharmacol 1994; 37: 75-78
    CrossrefPubMedGoogle Scholar
  • 9 Mroszczak EJ, Solish SB, Combs DL, Tsina I, Boyd A. Pharmacokinetics and interconversion of ketorolac enantiomers in humans. Clin Pharmacol Ther 1994; 55: 164
    PubMedGoogle Scholar
  • 10 Conrad KA, Fagan TC, Mackie MJ, Mayshar PV. Effects of ketorolac tro-methamine on hemostasis in volunteers. Clin Pharmacol Ther 1988; 43: 542-546
    CrossrefPubMedGoogle Scholar
  • 11 Levy M, Heyman A. Hematological adverse effects of analgesic-antiinflammatory drugs. Hematol Rev 1990; 4: 177-187
    PubMedGoogle Scholar
  • 12 Ibarra-Ibarra LG, Cubillo MA, Silva-Adaya A, Gonzalez-Garcia CA. Comparative study of ketorolac and dipyrone in the treatment of postoperative pain. Proc West Pharmacol Soc 1993; 36: 133-135
    PubMedGoogle Scholar
  • 13 Rodriguez MJ, de la Torre MR, Perez-Iraola P, Femandez-Cuervo C, Benitez P, Navarro A, Vidal J. Comparative study of tramadol versus NSAIDs as intravenous continuous infusion for managing postoperative pain. Curr Ther Res 1993; 54: 375-383
    CrossrefPubMedGoogle Scholar
  • 14 Patrono C, Ciabattoni G, Pinca E, Pugliese F, Castrucci G, de Salvo A, Satta MA, Peskar BA. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 1980; 17: 317-327
    CrossrefPubMedGoogle Scholar
  • 15 Peskar BA, Hertting G. Release of prostaglandins from isolated cat spleen by angiotensin and vasopressin. Naunyn-Schmiedeberg’s Arch Pharmac 1973; 279: 227-234
    PubMedGoogle Scholar
  • 16 Pallapies D, Peskar BA, Brune K, Geisslinger G. Effects on platelet functions and pharmacokinetics of azapropazone and ketorolac tromethamine given as single parenteral doses. Br J Clin Pharmacol 1994; 37: 335-339
    CrossrefPubMedGoogle Scholar
  • 17 Zylber-Katz E, Granit L, Drayer DE, Levy M. Simultaneous determination of dipyrone metabolites in plasma by high-performance liquid chromatography. J Chromatogr 1984; 305: 477-484
    CrossrefPubMedGoogle Scholar
  • 18 Wu A, Huang B, Massey I, Kushinsky S. Quantification of ketorolac in plasma and aquous humor by high-performance liquid chromatography. American Pharmaceutical Association 1986; Abstract P-48, San Francisco, March 16-20
    PubMedGoogle Scholar
  • 19 Jallad NS, Garg DC, Martinez JJ, Mroszczak EJ, Weidler DJ. Pharmacokinetics of single-dose oral and intramuscular ketorolac tromethamine in the young and elderly. J Clin Pharmacol 1990; 30: 76-81
    CrossrefPubMedGoogle Scholar
  • 20 Geisslinger G, Menzel-Soglowek S, Schuster O, Brune K. Stereoselective high-performance liquid chromatographic determination of flurbiprofen in human plasma. J Chromatogr 1992; 573: 163-167
    CrossrefPubMedGoogle Scholar
  • 21 Heinzel G, Woloszczak R, Thomann P. Topfit 2.0, pharmacokinetic and pharmacodynamic data analysis system for the PC. Stuttgart: Fischer 1993
    PubMedGoogle Scholar
  • 22 Holford NHG, Sheiner LB. Kinetics of pharmacologic response. Pharmac Ther 1982; 16: 143-166
    CrossrefPubMedGoogle Scholar
  • 23 Evans AM, Nation RL, Sansom LN, Bochner F, Somogyi AA. Effect of racemic ibuprofen dose on the magnitude and duration of platelet cyclo-oxygenase inhibition: relationship between inhibition of thromboxane production and the plasma unbound concentration of S(+)-ibuprofen. Br J Clin Pharmacol 1991; 31: 131-138
    CrossrefPubMedGoogle Scholar
  • 24 Bourne DWA. Boomer, a simulation and modeling program for pharmacokinetic and pharmacodynamic data analysis. Comput Methods Programs Biomed 1989; 29: 191-195
    CrossrefPubMedGoogle Scholar
  • 25 Gryglewski RJ. Screening and assessment of the potency of anti-inflammatory drugs in vitro. In: Anti-inflammatory drugs, handbook of experimental pharmacology 50/11. Vane JR, Ferreira SH, eds. Berlin: Springer 1979. 3-43
    PubMedGoogle Scholar
  • 26 Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971; 231: 232-235
    PubMedGoogle Scholar
  • 27 Eldor A, Zylber-Katz E, Levy M. The effect of oral administration of dipyrone on the capacity of blood platelets to synthesize thromboxane A2 in man. Eur J Clin Pharmacol 1984; 26: 171-176
    CrossrefPubMedGoogle Scholar
  • 28 Eldor A, Polliack G, Vlodavsky I, Levy M. Effects of dipyrone on prostaglandin production by human platelets and cultured bovine aortic endothelial cells. Thromb Haemost 1983; 49: 132-137
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Weiss VR, Brauer J, Goertz U, Petry S. Vergleichende Untersuchungen zur Frage der Absorption und Metabolisierung des Pyrazolonderivates Meta-mizol nach oraler und intramuskularer Gabe beim Menschen. Drug Res 1974; 24: 345-348
    PubMedGoogle Scholar
  • 30 Asmardi G, Jamali F. Pharmacokinetics of dipyrone in man; role of the administration route. Eur J Drug Met Pharmacokinet 1985; 10: 121-125
    PubMedGoogle Scholar