Pharmacokinetic analysis
The endpoints for the clinical study was the change in the area under the curve (AUC) of 4-MAA, 4-AA, 4-FAA and 4-AAA and of the terminal half-life (t1/2) of 4-MAA under the different conditions (placebo, ciprofloxacin, fluconazole, ciprofloxacin+fluconazole). These parameters were determined using non-compartmental methods with PKanalix (version 2019R1, Lixoft SAS, Abtony, France). AUC6h, 8h, 12h, 24h was assessed using the linear log trapezoidal method and t1/2 was calculated from the elimination rate constant, which was determined using linear regression of log concentrations and time.
To describe the influence of the inhibitors on the metabolism of metamizole, metabolic ratios were calculated. The impact on the formylation was described as\(\frac{\text{AUC}_{4-FAA}}{\text{AUC}_{4-MAA}}\), the demethylation as\(\frac{\text{AUC}_{4-AA}{\ +\ AUC}_{4-AAA}}{\text{AUC}_{4-MAA}}\), the acetylation as \(\frac{\text{AUC}_{4-AAA}}{\text{AUC}_{4-AA}}\)and the impact on the total metabolism of 4-MAA as\(\frac{\text{AUC}_{4-AA\ }{{+\ AUC}_{4-AAA}\ +\ AUC}_{4-FAA}}{\text{AUC}_{4-MAA}}\).
Both MR and AUCs were assessed at different time points due to the decreasing exposure of the participants to the inhibitors.