Table 1.
Drug-dependent parameters of carbamazepine and carbamazepine-10,11-epoxide.
| Parameter | Unit | Model | Literature | Reference |
|---|---|---|---|---|
| Carbamazepine | ||||
| Molecular weight | g/mol | 236.27 (Lit) | 236.27 | [38] |
| Lipophilicity | Log Units | 2.00 (Fit) | 1.45; 2.1; 2.45; 2.77 | [38,39,40] |
| Solubility (FaHIF) | µg/mL | 336 (Lit) | 170; 283; 306; 336 | [41,42,43,44] |
| Fraction unbound | % | 25 (Lit) | 21; 24; 25 | [45,46,47,48] |
| Km (CYP3A4) → CBZ-E | µM | 248 (Lit) | 119; 248; 442; 630 | [2,49,50,51] |
| kcat (CYP3A4) → CBZ-E | 1/min | 0.75 (Fit) | 1.17; 1.7; 4.87; 5.3 b | [2,49,50,51] |
| Km (CYP2C8) → CBZ-E | µM | 757 (Lit) | 757 | [50] |
| kcat (CYP2C8) → CBZ-E | 1/min | 0.67 (Lit) | 0.67 b | [50] |
| Km (CYP3A4) | µM | 282 (Lit) | 282 | [35] |
| kcat (CYP3A4) | 1/min | 0.20 (Fit) | 0.16 b | [35] |
| Km (CYP2B6) | µM | 420 (Lit) | 420 | [35] |
| kcat (CYP2B6) | 1/min | 0.43 (Lit) | 0.43 b | [35] |
| Km (UGT2B7) | µM | 214 (Lit) | 214 | [52] |
| kcat (UGT2B7) | 1/min | 9.53 × 10−3 (Lit) | 9.53 × 10−3 c | [52] |
| CLhep | 1/min | 0.02 (Fit) | - | - |
| GFR fraction | - | 0.03 (Fit) | - | - |
| EC50 (CYP3A4) | µM | 20.00 a (Lit) | 4.3–137 | [53,54,55,56,57,58,59,60] |
| Emax (CYP3A4) | - | 6.00 (Fit) | 1.9–23 | [53,54,55,56,57,58,59,60] |
| EC50 (CYP2B6) | µM | 20.00 a (Asm) | 22–145 | [60,61,62] |
| Emax (CYP2B6) | - | 17.00 (Fit) | 3.1–21.5 | [60,61,62] |
| EC50 (EPHX1) | µM | 20.00 a (Asm) | - | - |
| Emax (EPHX1) | - | 3.25 (Fit) | - | - |
| Intestinal permeability | cm/s | 4.3 × 10−4 (Lit) | 4.3 × 10−4 | [63] |
| Partition coefficients | - | Rodgers and Rowlands | [64,65] | |
| Cellular permeabilities | cm/s | PK-Sim Standard | [66] | |
| Carbamazepine-10,11-epoxide | ||||
| Molecular weight | g/mol | 252.27 (Lit) | 252.27 | [67] |
| Lipophilicity | Log Units | 1.00 (Fit) | 1.58; 1.97 | [67] |
| Solubility | µg/mL | 1340 (Lit) | 1340 | [67] |
| Fraction unbound | % | 51.8 (Lit) | 46.8; 49.0; 47.0; 51.8; 50.0 | [68] |
| CLspec (EPHX1) | 1/min | 0.01 (Fit) | - | - |
| GFR fraction | - | 0.21 (Fit) | - | - |
| Intestinal permeability | cm/s | 5.0 × 10−3 (Fit) | - | - |
| Partition coefficients | - | Rodgers and Rowlands | [64,65] | |
| Cellular permeabilities | cm/s | PK-Sim Standard | [66] | |
Asm: assumption, CBZ-E: carbamazepine-10,11-epoxide, CLhep: hepatic clearance, CLspec: specific clearance, CYP: cytochrome P450, GFR: glomerular filtration rate, EC50: half maximal effective concentration, Emax: maximum effect, EPHX1: epoxide hydroxylase 1, FaHIF: fasted human intestinal fluid, Fit: fitted in parameter optimization, Km: Michaelis−Menten constant, kcat: catalytic rate constant, Lit: literature, UGT: UDP-glucuronosyltransferase, Vmax: maximum reaction velocity. a mean of literature values of EC50 (CYP3A4), assumed for all EC50 values. b kcat values calculated within PK-Sim from Vmax/recombinant enzyme. c kcat value calculated within PK-Sim from Vmax = 0.79 pmol/min/microsomal protein, derived from in vitro assays in microsomes, assuming a microsomal UGT2B7 content of 82.9 pmol/mg microsomal protein [69]; kcat = Vmax/UGT2B7 content microsomes.