LACK OF INTERACTION BETWEEN ZIDOVUDINE AND 4-METHYL-AMINO-ANTIPYRINE,THE ACTIVE METABOLITE OF METAMIZOLE, IN HUMAN LIVER IN-VITRO

Zidovudine (AZT) is eliminated by extensive metabolism to an ether glu curonide (GAZT). The nonnarcotic analgesic metamizole (dipyrone) is a typical prodrug, the active metabolite being 4-methyl-amino-antipyrine (4-MAA). About 20% of 4-MAA is excreted in the form of glucuronide in the urine. The aim of this study was to investigate whether 4-MAA inh ibits the glucuronidation of AZT, by comparing the GAZT formed in the presence and absence of 4-MAA in the microsomal fractions. Microsomal fractions were obtained from 6 human livers. AZT and 4-MAA were added in concentrations of 1 mmole, corresponding to the therapeutically rel evant plasma concentrations of both drugs. Incubation time was 20 min. Concentrations of GAZT were measured using reverse-phase HPLC (high p erformance liquid chromatography). The mean value of GAZT formed in th e microsomal samples without the addition of 4-MAA was 1.87 +/- 074 pm ole/mg protein. In the presence of 4-MAA, the concentrations averaged 1.77 +/- 0.77 pmole/mg protein, and did nor differ significantly from those measured without 4-MAA. In conclusion the glucuronidation of AZT is not inhibited by 4-MAA, the main active metabolite of metamizole. From the in vitro findings it is predicted that concomitant metamizole administration may fail to enhance by metabolic interference the AZT concentrations under therapy.