Effect of ciprofloxacin and fluconazole on the plasma concentrations of 4-MAA, 4-AA, 4-AAA and 4-FAA
Treatment with ciprofloxacin increased the plasma concentrations of 4-MAA (Figure 3) and slowed its elimination (Table 1 and suppl. Figure 3), confirming that 4-MAA is metabolized by CYP1A2. Accordingly, the AUC0-12h and AUC0-24h increased by 51% and 66%, respectively (suppl. Table 1). The addition of fluconazole further slowed the elimination of 4-MAA and increased the AUC0-12h and AUC0-24h by 92% and 133%, respectively, compared to placebo. As expected, the formation of 4-AA, 4-FAA and 4-AAA was slowed and decreased by the administration of ciprofloxacin (Figure 3). The addition of fluconazole further slowed and decreased the formation of 4-FAA and 4-AAA, but not of 4-AA.
Similar to ciprofloxacin, also the treatment with fluconazole increased the plasma concentrations of 4-MAA (Fig. 3) and slowed its elimination (Table 1 and suppl. Figure 3). The increase in the AUC0-12h and AUC0-24h was 17% and 24%, respectively, approximately 5-times less than the corresponding increase by ciprofloxacin. The addition of ciprofloxacin further slowed the elimination of 4-MAA and increased the AUC0-12h and AUC0-24h of 4-MAA as described for ciprofloxacin. Fluconazole retarded and decreased the formation of 4-AA, 4-FAA and 4-AAA slightly with effects on the AUC only up to 8 h after ingestion of metamizole. The effect of ciprofloxacin, fluconazole and the combination ciprofloxacin/fluconazole on the AUC0-12h of the four metamizole metabolites is shown in suppl. Fig. 4. The figure shows that the inhibition of the metabolism of 4-MAA is much stronger for ciprofloxacin compared to fluconazole and that the reduction in the AUC0-12h by ciprofloxacin or fluconazole is more accentuated for 4-FAA than for 4-AA and 4-AAA.