Table 1.
Summary of physicochemical and pharmacokinetic properties of compounds
| Amikacin | Bosentan | Caffeine | Clindamycin | Diclofenac | Docetaxel | Itraconazole | Lorazepam | Midazolam | Montelukast | Ropivcaine | Sotalol | Theophyline | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| BCS | 3 | 3 | 1 | 1 | 2 | 2 | 2 | 2 | 1 | 2 | 2 | 3 | 1 |
| Indication | Severe sepsis | Pulmonary arterial hyper‐tension | Psychoactive agents | Infections | Infections | Cancer | Antifungal | Severe sepsis | CNS | Asthma | Visceral pain | Anti‐hypertensive | COPD |
| MW (g/mol) | 585.6 | 551.6 | 192.190 | 424.980 | 296.1 | 807.9 | 705.6 | 321.160 | 325.8 | 586.2 | 274.41 | 272.360 | 180.2 |
| log P | −7.4 | 3.7 | −0.07 | 2.160 | 4.5 | 3.2 | 5.66 | 2.4 | 3.53 | 8.98 | 2.91 | 0.370 | −0.02 |
| Compound type | Ampholyte | Acid | Base | Base | Acid | Neutral | Base | Ampholyte | Ampholyte | Acid | Base | Ampholyte | Ampholyte |
| pKas of acidic (pKa1) and basic (pKa2) centers |
pKa1 = 12.1 pKa2 = 9.8 |
pKa1 = 5.1 | pKa2 = 1.1 | pKa2 = 7.6 | pKa1 = 4.0 | — | pKa2 = 3.7 |
pKa1 = 11.5 pKa2 = 1.3 |
pKa1 = 10.95 pKa2 = 6.2 |
pKa1 = 5.7 | pKa2 = 8.07 |
pKa1 = 8.28 Pk2 = 9.72 |
pKa1 = 8.8. pKa2 = 0.99 |
| B/P | 1.00 | 0.60 | 0.98 | 0.94 | 1 | 0.68 | 0.58 | 0.642 | 0.603 | 0.65 | 0.94 | 1.02 | 0.82 |
| fu.p | 0.99 | 0.02 | 0.680 | 0.06 | 0.05 | 0.067 | 0.016 | 0.102 | 0.032 | 0.006 | 0.052 | 1 | 0.5 |
| Absorption parameters | — |
ADAM model. P eff.man = 1 × 10−4 cm/s. PSA = 145.65. HBD = 2. solubility FassiF = 20 mg/mL |
First order absorption Fa = 1. Ka = 2.03 |
— |
ADAM model. PSA = 52.16.HBD = 2.P eff.man = 10 × 10−4 cm/s Solubility FassiF = 0.805 mg/mL |
— | — | — |
ADAM model. Caco‐2 PH7.4:7.4 Passive & Active = 213 × 10−6 cm/s. P eff.man = 6.0 × 10−4 cm/s |
ADAM model. PSA = 95.72. HBD = 2. P eff.man = 0.3 × 10‐4 cm/s |
— |
First order absorption Fa = 1. Ka = 0.44 |
First order absorption fa = 1. ka = 6 |
| Main elimination pathway | Renal (100%) | Metabolism (97%), renal (3%) | Metabolism (99%), renal (1%) |
Metabolism (95%), Renal (5%) |
Metabolism (98%) renal (2%) |
Metabolism (83%), bile (4%), Renal (4%), additional (9%) | Metabolism (100%) |
Metabolism (95%) renal (5%) |
Metabolism (100%) | Metabolism (100%) |
Metabolism (99%). renal (1%) |
Renal (100%) |
Metabolism (90%) renal (10%) |
| Fractional contribution of individual CYPs/UGT | — |
CYP3A4 (60%). CYP2C9 (40%) |
CYP1A2 (98%). CYP2E1 (2%) |
CYP3A4 (88%). CYP3A5 (12%) |
CYP2C9 (100%) |
CYP3A4 (95%) CYP3A5 (5%) |
CYP3A4 (98%) CYP1A2 (2%) |
— | CYP3A4 (100%) |
CYP2C8 (72%) CYP3A4 (16%) CYP2C9 (12%) |
CYP1A2 (92%). CYP3A4 (8%) |
— |
CYP1A2, (75%) CYP2D6 (7%) CYP2E1 (10%) CYP3A4 (8%) |
| In vitro intrinsic clearance (μL/min/pmol P450) | — |
CLint CYP3A4 = 0.85 CYP2C9 = 1.07 |
CYP1A2 = 0.047 CYP1E2 = 0.000829 |
CLint CYP3A4 = 0.7 CLint CYP3A5 = 0.13 |
CLint CYP2C9 = 25.06 |
CLint CYP3A4 = 1.7 CLint CYP3A5 = 0.23 |
CYP3A4: HLM. V max = 18 pmol/min/mg. Km = 0.023 μM CLint 1A2 = 1 μL/min/mg |
CLint (UGT2B7) = 9.97 μL/min/pmol | CLint 3A4 = 3.74 |
CLint CYP2C8 = 3.68 CLint CYP3A4 = 0.13. CLint CYP2C9 = 0.18 |
CLint CYP1A2 = 2.41 CLint CYP3A4 = 0.08 |
— |
CLint CYP1A2 = 0.02 CLint CYP2D6 = 0.011 CLint CYP2E1 = 0.0022 CLint CYP3A4 = 0.00078 |
| References | Drug Bank | 23, 26, 27 | Simcyp | 12, 28 | 29, 30 | 9, 20 | Simcyp, 31 | Simcyp | Simcyp | 32, 33, 34 | 35, 36 | Drug Bank | Simcyp |
B/P, blood to plasma partition ratio; BCS, biopharmaceutical classification system; Caco‐2, Caco‐2 permeability (10−6 cm/s); CLint, in vitro intrinsic clearance; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; fa, fraction available from dosage form; fu.p, fraction unbound in plasma; fuGut, unbound fraction of drug in enterocytes; HBD, number of hydrogen bond donors; ISEF, intersystem extrapolation factor for scaling of recombinant CYP in vitro kinetic data; IV, intravenous therapy; ka, first‐order absorption rate constant (L/h); Km, Michaelis‐Menten constant (μM); log P, lipophilicity; MRT, mean residence time; MW, molecular weight; P eff.man, human jejunum effective permeability (10−4 cm/s); pKa, acid/base character; PO, oral administration; PSA, polar surface area; Q Gut, a nominal flow in gut model (L/h); V max, maximum rate of metabolite formation.