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The Potentially Significant Role of CYP3A-Mediated Oxidative Metabolism of Dabigatran Etexilate and its Intermediate Metabolites in Drug-Drug Interaction Assessments Using Microdose Dabigatran Etexilate

Udomsak Udomnilobol, Suree Jianmongkol and Thomayant Prueksaritanont
Drug Metabolism and Disposition May 25, 2023, DMD-AR-2023-001353; DOI: https://doi.org/10.1124/dmd.123.001353

Data Supplement

  • Supplemental Data -

    Supplemental Table S1. BIBR0951 and its metabolites detected in the NADPH-fortified incubations.

    Supplemental Table S2. DABE and its metabolites detected in NADPH-fortified incubations.

    Supplemental Table S3. Formation kinetic of primary metabolites following incubation of either DABE or BIBR0951 in NADPH-fortified rhCYP3A4 and rhCYP3A5.

    Supplemental Figure S1. Stability of DABE (A), BIBR0951 (B), and BIBR1087 (C) in the phosphate buffer fortified with NADPH (no microsomal protein).

    Supplemental Figure S2. Effects of KTZ (1 µM) and BNPP (100 µM) on the formation of BIBR0951 (A), M644 (1) and (2) (B), M264 (C), BIBR1087 (D), and M528 (E) following incubation of 1 µM DABE in HIM with (left panel) or without (right panel) NADPH.

    Supplemental Figure S3. Effects of KTZ (1 µM) and BNPP (100 µM) on the formation of DAB (A), M400 (B), M516 (1) (C), M516 (2) (D), M498 (1) (E), and M498 (2) (F) following incubation of 1 µM BIBR0951 in HIM with (left panel) or without (right panel) NADPH.

    Supplemental Figure S4. Effects of KTZ (1 µM) and BNPP (100 µM) on the formation of DAB (A), M400 (B), M516 (1) (C), M516 (2) (D), M498 (1) (E), and M498 (2) (F) following incubation of 1 µM BIBR0951 in HLM with (left panel) or without (right panel) NADPH.

    Supplemental Figure S5. Plots of in vitro depletion rate constants (kdep) of DABE (A) and BIBR0951 (B) versus concentrations in the NADPH-fortified rhCYP3A4 and rhCYP3A5 systems.

    Supplemental Figure S6. Michaelis-Menten kinetics of CES-mediated hydrolysis of DABE (A and B) and BIBR0951 (C) in HLM and HIM. Data are expressed as mean ± SD from n=3.

    Supplemental Figure S7. The formation of M644 (1) and (2) (A), M264 (B), BIBR1087 (C), and M528 (D) following incubation of DABE in NADPH-fortified rhCYP3A4 and rhCYP3A5 systems.

    Supplemental Figure S8. The formation of DAB (A), M400 (B), M516 (1) (C), M516 (2) (D), M498 (1) (E), and M498 (2) (F) following incubation of BIBR0951 in NADPH-fortified rhCYP3A4 and rhCYP3A5 systems.

    Supplemental Figure S9. Metabolic stability of DAB (1 µM) in HLM (0.5 mg/mL).

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