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 glucuronide (GAZT). The nonnarcotic analgesic metamizole (dipyrone) is a typical polydrug, 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 inhibits 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 relevant plasma concentrations of both drugs. Incubation time was 20 min. Concentrations of GAZT were measured using reverse-phase HPLC (high performance liquid chromatography). The mean value of GAZT formed in the microsomal samples without the addition of 4-MAA was 1.87 +/- 0.74 pmole/mg protein. In the presence of 4-MAA, the concentrations averaged 1.77 +/- 0.77 pmole/mg protein, and did not 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.
Bacracheva
N
N
Department of Clinical Pharmacology, Medical Faculty, Sofia, Bulgaria.
Kamali
F
F
D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D004177:Dipyrone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D047069:Pyrazolones; D044465:White People; D015215:Zidovudine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology
D000998:Antiviral Agents; D005965:Glucuronates; D047069:Pyrazolones; D015215:Zidovudine; D004177:Dipyrone; C055886:3'-azido-3'-deoxy-5'-O-beta-glucopyranuronosylthymidine; C008667:noramidopyrine