TABLE 5.
In vitro disposition properties of NDD-713 and -825
| Parameter | Assay | Units | NDD-713 | NDD-825 |
|---|---|---|---|---|
| Lipophilicity | Distribution coefficient, pH 3 | gLogDpH 3 | 1.7 | 1.5 |
| Distribution coefficient, pH 7.4 | gLogDpH 7.4 | 2.3 | 2.0 | |
| Solubilitya | Aqueous, at pH 2.0 | Saq (μg/ml) | >100 | >100 |
| Aqueous, at pH 6.5 | Saq (μg/ml) | 25–50 | 50–100 | |
| Permeabilitya | Bidirectional CaCo-2 | Papp, A-B (10−6 cm/s) | 25 ± 4 | 6.5 ± 0.5 |
| Mass balance | A-B (%) | 76 ± 10 | 79 ± 11 | |
| Efflux ratio | Papp, B-A/Papp, A-B | <3 | <3 | |
| Protein binding | Plasma protein | PPB (%) | 63.5 | 73.5 |
| Human plasma | fu | 0.15 | 0.01 | |
| Rat plasma | fu | 0.16 | 0.11 | |
| Human liver microsomes | fu | 0.67 | 0.63 | |
| Metabolic stability | Human liver microsomesb | CLint (μl/min/mg) | <0.16 | <0.16 |
| Rat liver microsomesb | CLint (μl/min/mg) | <0.1 | 0.18 ± 0.2 | |
| Human hepatocytesb | CLint (μl/min/106 cells) | <6 | 6 | |
| Rat hepatocytesb | CLint (μl/min/106 cells) | minimal | 5 | |
| Rat liver cytosolic fractionb | CLint (μl/min/mg) | <1.4 | <1.4–1.7 | |
| Metabolisma | P450 in vitro clearancec | CLint (μl/min/pmol P450) | 0.02,d,g 0.07e,g | 0.02,f,g 0.17e,g |
| P450 inhibitionh | IC50 (μM) | >20 | >20 |
Values and ranges quoted are averages of 2 (or 3 where means ± sd are shown) separate determinations. aThe hydrochloride salts of NDD-713 and -825 were used. bIn the presence of NAD+, NADPH, or in the absence of cofactors. cAssayed: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4. dCYP2A6. eCYP3A4. fCYP2D6 and CYP2E1. gNDD-713 and -825 were not observed to be metabolized by other P450 isoforms assayed. hCYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5.