| Autor: |
Li XQ; Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden., Thelingwani RS; Department of Pharmaceutical Medicine, African Institute of Biomedical Science and Technology (AiBST), Block C, Wilkins Hospital Complex, Harare, Zimbabwe., Bertilsson L; Division of Clinical Pharmacology-C1:68, Department of Laboratory Medicine at Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden., Diczfalusy U; Division of Clinical Chemistry, Department of Laboratory Medicine at Karolinska Institutet, Karolinska University Hospital (Huddinge), SE-141 86 Stockholm, Sweden., Andersson TB; Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden., Masimirembwa C; Department of Pharmaceutical Medicine, African Institute of Biomedical Science and Technology (AiBST), Block C, Wilkins Hospital Complex, Harare, Zimbabwe. |
| Abstrakt: |
In this study, we aimed to evaluate the utility of endogenous 1β-hydroxy-deoxycholic acid/total deoxycholic acid ratio (1β-OH-DCA/ToDCA) in spot urine as a surrogate marker of cytochrome P450 3A (CYP3A) activity in the assessment inhibition-based drug-drug interactions in healthy volunteers. This was accomplished through an open-label, three-treatment parallel-arm study in healthy male volunteers from Zimbabwe. Each group received itraconazole (ITZ; 100 mg once daily; n = 10), fluconazole (FKZ; 50 mg once daily; n = 9), or alprazolam (APZ; 1 mg once daily; n = 8) orally. Midazolam (MDZ), dosed orally and intravenously, was used as a comparator to validate the exploratory measures of CYP3A activity and the effects of known inhibitors. Urinary metabolic ratios of 1β-OH-DCA/ToDCA before and after CYP3A inhibitor treatment showed a similar magnitude of inhibitory effects of the three treatments as that measured by oral MDZ clearance. The maximum inhibition effect of a 75% reduction in the 1β-OH-DCA/ToDCA ratio compared to the baseline was achieved in the ITZ group following six once-daily doses of 100 mg. The correlations of the two markers for CYP3A inhibitor treatment were significant (r s = 0.53, p < 0.01). The half-life of urinary endogenous 1β-OH-DCA/ToDCA was estimated as four days. These results suggested that 1β-OH-DCA/ToDCA in spot urine is a promising convenient, non-invasive, sensitive, and relatively quickly responsive endogenous biomarker that can be used for CYP3A inhibition-based drug-drug interaction in clinical studies. |
