Table 4.
Bumped Kinase Inhibitor (BKI) related gastrointestinal and systemic toxicity in mice
| BKI | Dose at which toxicity was observed (mg/kg) | Observed toxicity | Observed maximum plasma exposure at toxic dose (μM) | Observed maximum gastrointestinal tissue exposure after single dose (μM) |
|---|---|---|---|---|
| 1369 | 300 (QD in mice) | Interference with digestion and peristalsis | 8.3 ± 0.2 | 30 mg/kg dose: 76 ± 41 (duodenum) 39 ± 4 (jejunum/ileum) 20 ± 6 (cecum) 23 ± 9 (ascending colon) |
| 1534 | 100 (QD in mice) 10 (BID in calves) | Interference with digestion and peristalsis | 1.8 ± 0.9 | ND |
| 1553 | 150 (QD in mice) 15 (BID in calves) | Interference with digestion and peristalsis, gastric bleeding in mice and calves | 102 ± 20 | 10 mg/kg dose: 41 ± 35 (duodenum) 56 ± 14 (jejunum/ileum) 9 ± 1.5 (cecum) 27 ± 3 (ascending colon) |
| 1608 | 100 (QD in mice) | Interference with digestion and peristalsis | 9.9 ± 3 | ND |
| 1649 | 50 (QD in mice) | Extreme signs of distress after 7 doses, including lack of grooming, weight loss, lethargy, hunched posture | 307 ± 27 | ND |
| 1673 | 250 (QD in mice) | Slight signs of distress after 7 doses, including lack of grooming, weight loss | 72 ± 5 | ND |
| 1749 | 60 (QD in mice) | GI tissue inflammation | ND | ND |
| 1751 | 60 (QD in mice) | Signs of distress after 4 doses, including lack of grooming, weight loss, lethargy | 25 ± 6 | ND |
| 1779 | 60 (QD in mice) | GI tissue inflammation | ND | ND |
ND, not determined; QD, once daily; BID, twice daily; GI, gastrointestinal