CLINICAL PHARMACOKINETICS OF DIPYRONE AND ITS METABOLITES

The pharmacokinetics of dipyrone are characterised by rapid hydrolysis to the active moiety 4-methyl-amino-antipyrine (MAA), which has 85% b ioavailability after oral administration in tablet form, and takes a s hort time to achieve maximal systemic concentrations (t(max) of 1.2 to 2.0 hours), Absolute bioavailability after intramuscular and rectal a dministration is 87 and 54%, respectively. MAA is further metabolised with a mean elimination half-life (t(1/2)) of 2.6 to 3.5 hours to 4-fo rmyl-amino-antipyrine (FAA), which is an end-metabolite, and to 4-amin o-antipyrine (AA), which is then acetylated to 4-acetyl-amino-antipyri ne (AAA) by the polymorphic N-acetyl-transferase (t(1/2) of AA is 3.8 hours in rapid acetylators and 5.5 hours in slow acetylators), Urinary excretion of these 4 metabolites accounts for about 60% of the admini stered dose of dipyrone, Protein binding of the 4 main metabolites is less than 60% The volume of distribution of MAA is about 1.15 L/kg of lean body mass. All 4 metabolites are excreted into breast milk. A sin gle-dose study (0.75, 1.5 and 3g) and a multiple-dose study (1g 3 time s a day for 7 days) revealed nonlinear pharmacokinetics consistent wit h a shift of MAA metabolism from FAA to AA. Apparent MAA clearance dec reased by 22% during multiple administration, MAA clearance was reduce d by 33% in the elderly. In patients with cirrhosis of the liver, the apparent clearance of all metabolites is generally reduced. In patient s with renal disease, apparent clearance of MAA remains unchanged, whe reas elimination of the renally excreted metabolites AAA and FAA is ma rkedly impaired. No clinically important drug interactions have thus f ar been recognised. Dipyrone does not affect the pharmacodynamic respo nse to alcohol(ethanol), glibenclamide (glyburide), oral anticoagulant s or furosemide (frusemide). The low toxicity of dipyrone and its effi cacy support its use in clinical practice, despite some complex aspect s of its disposition.