TABLE 6.
Summary of inhibitory effects of delamanid and its metabolites on ATP-binding cassette transporters and solute carriersa
| Transporter | IC50 (μmol/liter)a |
Cmax/IC50b |
(50 × Cmax,u)/IC50b,c |
||||||
|---|---|---|---|---|---|---|---|---|---|
| Delamanid | M1 | M2 | M3 | M4 | M1 | M2 | M1 | M2 | |
| MDR1 | (>5) | 4.65 | 7.80 | (>3) | (>3) | 0.07 | 0.02 | 0.010 | 0.002 |
| BCRP | (>5) | 5.71 | 6.02 | (>3) | (>3) | 0.06 | 0.02 | 0.008 | 0.003 |
| OAT1B1 | (>5) | (>10) | (>10) | (>3) | (>3) | —d | — | — | — |
| OATP1B3 | (>5) | (>10) | (>10) | (>3) | (>3) | — | — | — | — |
| OAT1 | (>5) | (>10) | (>10) | (>3) | (>3) | — | — | — | — |
| OAT3 | (>5) | (>10) | (>10) | (>3) | (>3) | — | — | — | — |
| OCT1 | (>5) | (>10) | (>10) | (>3) | (>3) | — | — | — | — |
| OCT2 | (>5) | (>10) | (>10) | (>3) | (>3) | — | — | — | — |
| BSEP | (>5) | (>10) | (>10) | (>5) | (>3) | — | — | — | — |
The values in parentheses represent the maximum concentration of the test compound in the inhibition study and indicate that 50% inhibition was not observed even at the maximum concentration tested.
The Cmax/IC50 and (50 × Cmax,u)/IC50 values were calculated using the Cmax of the corresponding metabolite in human plasma after repeated administrations of delamanid at 100 mg twice a day for 56 days (22).
The unbound fraction of M1 in plasma in vitro was determined as described previously (22), and the unbound fraction of M2 was assumed to be equivalent to that of M1.
—, not applicable. Cmax/IC50 and (50 × Cmax,u)/IC50 were not calculated for delamanid, M3, and M4 because they showed no potency against the transporters.