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.