Article Figures & Data
Figures
- Fig. 1.
Structure of [14C]dasabuvir and synthetic metabolites.
- Fig. 2.
Mean cumulative percent of radioactive dose recovered in urine and feces at specified intervals after a single 400-mg (100 µCi) oral dose of [14C]dasabuvir to healthy male subjects.
- Fig. 3.
Mean (S.D.) plasma concentration-time curves for dasabuvir (in nanograms per milliliter) and total radioactivity (in nanogram equivalents per gram) in male subjects administered a single 400-mg oral dose of [14C]dasabuvir (N = 4).
- Fig. 4.
Representative HPLC radiochromatograms of dasabuvir and its metabolites in human plasma after a single 400-mg oral dose of [14C]dasabuvir. CPM, counts per minute.
- Fig. 5.
Representative HPLC radiochromatograms of dasabuvir and its metabolites in human excreta, urine (A) and feces (B), after a single 400-mg oral dose of [14C]dasabuvir. CPM, counts per minute; RT, retention time.
- Fig. 6.
Proposed metabolic pathways of dasabuvir in humans.
- Fig. 7.
Representative HPLC radiochromatograms of dasabuvir and its metabolites in recombinant human CYP2C8 (A), CYP3A4 (B), CYP2D6 (C) and CYP2B6 (D) isoforms.
Tables
- TABLE 1
Pharmacokinetic parameters of total radioactivity, dasabuvir, and metabolite M1
Data are presented as means ± S.D.
Analyte Cmax Tmax AUC0–last AUC0–∞ t1/2 ngEq/g or ng/ml h ngEq/g or ng/ml h Total radioactivity 1300 ± 586 4 ± 0 8251 ± 3111 9959 ± 3414 Dasabuvir 658 ± 252 4 ± 0 6260 ± 1930 6290 ± 1930 8.4 ± 3.2 M1 267 ± 116 3.0 ± 1.2 2230 ± 948 2280 ± 934 6.2 ± 1.3 t1/2, half-life.
- TABLE 2
Percentages of radioactivity for dasabuvir and corresponding metabolites in human plasma (N = 4) after administration of a single 400-mg oral dose of [14C]dasabuvir
Data are presented as means ± S.D.
Metabolite Percentage of Radioactivity in Plasma Dasabuvir 58.1 ± 4.6 M1 21.4 ± 2.4 M2 6.6 ± 2.4 M3 4.4 ± 3.0 M4 1.7 ± 1.3 M5 1.7 ± 1.7 M6 2.3 ± 2.0 U1 4.7 ± 1.1 - TABLE 3
Percentages of excretory metabolites of dasabuvir in humans (N = 4) after administration of a single 400-mg oral dose of [14C]dasabuvir
Metabolite Feces Urine Total 0–216 h 0–24 h Total radioactivity 94.4 2.20a 96.6 Dasabuvir 26.2 0.03 26.2 M1 31.5 0.85 32.4 M2 15.2 0.3 15.5 M3 ND 0.19 0.19 M4 ND 0.12 0.12 M5 11.1 0.12 11.2 M6 ND 0.02 0.02 M7 ND 0.38 0.38 M8 2.05 ND 2.05 M9 4.91 ND 4.91 M10 3.37 ND 3.37 M11 ND 0.03 0.03 U1 ND 0.01 0.01 ND, not determined.
↵a Total radioactivity for urine is 0–216 hours.
- TABLE 4
Retention time, molecular ions, and characteristic fragment ions of dasabuvir and metabolites in human plasma, urine, or feces
Compound Observed [M-H]− Theoretical [M-H]− Mass Error Metabolite ID CharacteristicFragment Ionsb ppm Dasabuvir 492.1601 492.1599 0.41 Parent drug 477c (−CH3), 462 (−2 CH3), 449 (−NCO), 435 (−C4H9), 414 (−SO2CH2), 399 (−SO2CH2 and −CH3) M1 508.1550 508.1548 0.39 P +O 493c (−CH3), 476 (−CH3OH), 463 (−C2H5O), 435 (−C4H9O), 430 (−SO2CH2), 415 (−SO2CH2 and −CH3), 399 (−SO2CH2 and −CH3O) M2 588.1111 588.1116 −0.85 M1 sulfate 545 (−NCO), 509c (−CH3SO2), 494 (−CH3SO2 and −CH3), 466 (−NCO and −CH3SO2), 465 (−NCO and −SO3), 433 (−NCO and −CH4SO4) M3 684.1861 684.1869 −1.17 M1 glucuronide 641 (−NCO), 597 (−NCO and −CO2), 476c (−C7H12O7), 433 (−C7H12O7 and −NCO) M4 506.1381 506.1391 −1.98 M1 −2H 463c (−C2H3O), 435 (−C4H7O), 413 (−SO2CH2 and −CH3) M5 522.1337 522.1340 −0.57 P +2O, −2H 507 (−CH3), 478 (−CO2), 463c (−C2H3O2), 435 (−C4H7O2) M6 698.1657 698.1661 −0.57 M5 glucuronide 522 (−C6H8O6), 478c (−C6H8O6 and −CO2), 463(−C6H8O6, −CO2, and −CH3), 383 (−C6H8O6, −CO2, −CH3, −CH4SO2) M7 700.1801 700.1818 −2.43 M6 +2H 524c (−C6H8O6), 444 (−C6H8O6 and −CH4SO2) M8a 524.1487 524.1497 −1.91 M5 +2H 480 (−CO2), 465c (−C2H3O2), 437 (−C4H7O2), 401 (−CO2 and −CH3SO2), 387 (−CO2, −CH2SO2, and −CH3) M9a 510.1694 510.1704 −1.96 M1 +2H 495c (−CH3), 478 (−CH3OH), 465 (−C2H5O), 452, 437 (−C4H9O) M10a 590.1260 590.1272 −2.03 M2 +2H N/A M11 494.1380 494.1391 −2.33 M1 –CH2 479c (−CH3), 464 (−2 CH3), 416 (−SO2CH2), 401 (−SO2CH2 and −CH3)
Data Supplement
Files in this Data Supplement:
- Supplemental Data -
Additional MS/MS Spectra of metabolites
- Supplemental Data -
In this issue
Metabolism and Disposition of [14C]Dasabuvir in Humans
