Table 4.
Pharmacokinetic properties ADMET analyses of absorption, distribution, excretion, metabolism, toxicity, and drug-likeness assessment.
| ADMET | Carvedilol | 1-hydroxyl carvedilol | 3-hydroxyl carvedilol | 4-hydroxyl carvedilol | 5-hydroxyl carvedilol | 8-hydroxyl carvedilol | O-desmethyl carvedilol |
|---|---|---|---|---|---|---|---|
| Physicochemical Properties | |||||||
| Molecular Weight | 406.47 | 422.47 | 422.47 | 422.47 | 422.47 | 422.47 | 392.45 |
| H-bond acceptors | 5 | 6 | 6 | 6 | 6 | 6 | 5 |
| H-bond donors | 3 | 4 | 4 | 4 | 4 | 4 | 4 |
| Number of rings | 4 | 4 | 4 | 4 | 4 | 4 | 4 |
| Number of carbons | > 4 | > 4 | > 4 | > 4 | > 4 | > 4 | > 4 |
| Rotatable bonds | 10 | 10 | 10 | 10 | 10 | 10 | 9 |
| Heteroatoms | 6 | 7 | 7 | 7 | 7 | 7 | 6 |
| TPSA | 75.74 | 95.97 | 95.97 | 95.97 | 95.97 | 95.97 | 86.74 |
| Lipophilicity | |||||||
| iLOGP | 3.45 | 2.15 | 3.2 | 2.31 | 3.41 | 3.08 | 2.48 |
| XLOGP3 | 4.37 | 4.01 | 4.01 | 4.01 | 4.01 | 4.01 | 4.1 |
| WLOGP | 3.74 | 3.44 | 3.44 | 3.44 | 3.44 | 3.44 | 3.44 |
| MLOGP | 1.96 | 1.43 | 1.43 | 1.43 | 1.43 | 1.43 | 1.75 |
| Consensus Log P | 3.61 | 3.02 | 3.23 | 3.05 | 3.27 | 3.21 | 3.15 |
| Pharmacokinetics | |||||||
| GI absorption | High | High | High | High | High | High | High |
| BBB permeant | Yes | No | No | No | No | No | No |
| Pgp substrate | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| CYP1A2 inhibitor | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| CYP2C19 inhibitor | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| CYP2C9 inhibitor | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| CYP2D6 inhibitor | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| CYP3A4 inhibitor | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| log Kp (cm/s) | − 5.68 | − 6.03 | − 6.03 | − 6.03 | − 6.03 | − 6.03 | − 5.78 |
| Drug-likeness | |||||||
| Lipinski (Pfizer) | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Egan (Pharmacia) | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Muegge (Bayer) | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Bioavailability | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 | 0.55 |
Criteria for Lipinski (Pfizer) filter: molecular weight ≤ 500, H-bond acceptors ≤ 10, H-bond donors ≤ 5, MLOGP ≤ 4.15; Criteria for Egan (Pharmacia) filter: WLOGP ≤ 5.88, TPSA ≤ 131.6; Criteria for Muegge (Bayer) filter: 200 ≤ molecular weight ≤ 600, -2 ≤ XLOGP ≤ 5, TPSA ≤ 150, number of rings ≤ 7, number of carbon > 4, Rotatable bonds ≤ 15, Heteroatoms > 1, H-bond acceptors ≤ 10, H-bond donors ≤ 5.
TPSA: Topological polar surface area; iLOGP, XLOGP3, WLOGP, MLOGP, and Silicos-IT Log P are five methods used to calculate the n-octanol/water partition coefficient (log Po/w); Consensus Log P: coefficient average value calculated by the aforementioned five methods; GI absorption: Gastrointestinal absorption; BBB permeant: blood–brain barrier permeant; Pgp substrate: P-glycoprotein substrate; CYP1A2: Cytochrome P450 1A2; CYP2C19: Cytochrome P450 2C19; CYP2C9: Cytochrome P450 2C9; CYP2D6: Cytochrome P450 2D6; CYP3A4: Cytochrome P450 3A4; log Kp (cm/s): Skin permeability coefficient.