Pharmacokinetics of dipyrone in man; role of the administration route

Pharmacokinetics of dipyrone, an aminopyrine derivative and potent analgesic, were studied in human following cross-over oral (p.o.) and intravenous (i.v.) administration of single one g doses to 6 subjects. High-performance liquid chromatographic (HPLC) methods were used to follow the drug and its active metabolite, 4-monomethylaminoantipyrine (MAA) in plasma and urine of subjects. Following p.o. doses, no unchanged dipyrone was detectable in plasma and urine. MAA appeared in plasma no later than 0.5 h after oral doses and reached its maximum concentration (7.52-22.69 micrograms/ml) in 1-2 h. Pharmacokinetic characteristics of MAA indicated a two and a one-compartment open model after i.v. and p.o. administration, respectively. Elimination half-life of MAA was found to be independent of the route of administration and ranged from 1.60 to 3.67 h. Although no significant difference was noticed between the area under plasma MAA concentration-time curves, 2.2-7.5 folds higher MAA was found unchanged in urine following i.v. administration (34.41-158.38 mg) as compared to the oral route (9.56-43.92 mg). It is suggested that after oral administration, dipyrone is rapidly and to a great extent converted to MAA during the first pass through the gut and/or liver before reaching the systemic circulations. Following i.v. administration, on the other hand, a relatively slower process of dipyrone conversion may allow a significant renal excretion of dipyrone which, in turn, is converted to MAA in the kidney and/or urine thereby giving rise to a significantly higher MAA in urine.