Table 1.
Inputs for atorvastatin and atorvastatin lactone substrate files
| Atorvastatin | O‐hydroxyatorvastatin | Atorvastatin lactone | O‐hydroxyatorvastatin lactone | |||||
|---|---|---|---|---|---|---|---|---|
| Value | Source | Value | Source | Value | Source | Value | Source | |
| Model file(s) | 1 and 2 | 1 and 2 | 2 | 2 | ||||
| Compound (file) | Sub (1)/Pri Met 1 (2) | Pri Met 1 (1)/Sec Met (2) | Sub (2) | Pri Met 2 (2) | ||||
| MW | 559 | ChemAxon | 574 | ChemAxon | 541 | ChemAxon | 556 | ChemAxon |
| logP | 5.39 | ChemAxon | 5.39 | Assumedb | 6.05 | ChemAxon | 6.05 | Assumedb |
| pK a (type) | 4.33 (Monoprotic acid) | ChemAxon | 4.33 (Monoprotic acid) | Assumedb | Neutral | ChemAxon | Neutral | Assumedb |
| B:P | 0.55 | Default (acid) | 0.55 | Default (acid) | 1 | Default (base) | 1 | Default (base) |
| fup | 0.022 | In house | 0.022 | Assumedb | 0.012 | In silico predicted | 0.012 | Assumedb |
| Absorption | ADAM | ADAM | ||||||
| Papp type | CaCo‐2; pH 6.5:7.4 | Wu et al. (2000)32 | — | — | MDCK | In house | — | — |
| Papp (cm/sx × 10−6) | 28.4 | — | — | 33 | — | — | ||
| Peff (10−4 cm/second) | 4.49 | Simcyp predicted | — | — | 8.34 | Simcyp predicted | — | — |
| Formulation | Solution with precipitation | — | — | Solution with precipitation | — | — | ||
| pH/solubility (mg/mL) | 2.1/0.0212 3.1/0.0321 4.1/0.0796 5/0.127 5.4/0.227 6/1.22 | Kearney et al. (1993)12 | — | — | 0.00134 (not pH dependent) | Kearney et al. (1993)12 | — | — |
| Stomach degradation (1/hour) | 50 | Optimizedc | — | — | — | — | — | — |
| Distribution | Full | Full (minimal as Sec Meta) | Minimal | Minimal | ||||
| Vdss (L/kg) | Simcyp predicted | Simcyp predicted | Simcyp predicted | Simcyp predicted | ||||
| Kp scalar | 2 | Optimized to reproduce Cmax at 40 mg | 1 | Default | 0.02 | Optimized to reproduce observed half‐life | 0.008 | Optimized to reproduce observed half‐life |
| Elimination | Enzyme kinetics (metabolite formed in parentheses) | |||||||
| CYP3A4 (Vmax/Km, μL/minute/mg) | 1,353/33 (o‐OHATV) | Jacobsen et al. (2000)14 | — | — | 1,397/1.6 (o‐OHATV lactone) | Jacobsen et al. (2000)14 | — | — |
| CYP3A4 (Vmax/Km, μL/minute/mg) | 1,048/34.8 | Jacobsen et al. (2000)14 | — | — | 3229/1.8 | Jacobsen et al. (2000)14 | — | — |
| UGT1A3 (μL/minute/mg) | 6.2 | Goosen et al. (2007)9 | — | — | — | — | — | — |
| Other HLM (μL/minute/mg) | 65 | Optimizedc | (500 as Sec Meta) | ECM | 1,500 | Optimizedc | 1,200 | Optimizedc |
| Plasma esterase (t1/2, minute) | — | — | — | — | 4 (atorvastatin) | Optimizedc | — | — |
| User ES (μL/minute/mg) | — | — | — | — | — | — | 7,000 (o‐OHATV) | Optimizedc |
| Transport (μL/106 cell second/minute) | ||||||||
| OATP1B1 (SF) | 31.5 (30) | In house/optimizedc | 25 (30)a | In house/optimizedc | — | — | — | — |
| OATP1B3 (SF) | 31.5 (30) | In house/optimizedc | 25 (30)a | In house/optimizedc | — | — | — | — |
| CLpd | 13 | In house | 5a | In house | — | — | — | — |
| CLbile | — | — | 10a | Optimized to reproduce 40 mg AUC | — | — | — | — |
| CLefflux | — | — | 15a | Optimized to reproduce Cmax/Tmax | — | — | — | — |
Model file 1 refers to that of atorvastatin (acid), and model file 2 refers to that of atorvastatin lactone.
ADAM, advanced dissolution, absorption, and metabolism; AUC, area under plasma concentration‐time curve; B:P, blood‐to‐plasma ratio; Cmax, maximum plasma concentration; CLbile, intrinsic biliary clearance; CLefflux, intrinsic sinusoidal efflux clearance; CLpd, intrinsic passive clearance; CYP3A4, cytochrome P450 3A4; ECM, extended clearance model; ES, esterase; Fup, fraction unbound in plasma; HLM, human liver microsomal clearance (non‐CYP3A4); logP, log octanol:water partition coefficient; Km, concentration at half maximal rate of metabolism; Kp, tissue partition coefficient; MW, molecular weight; o‐, ortho; OATP1B1 and 1B3, organic anion transporting polypeptides 1B1 and 1B3; OHATV, hydroxyatorvastatin; Papp, apparent in vitro permeability; Peff, effective in vivo permeability; pKa, log acid dissociation constant; Pri Met 1 and Pri Met 2, included as primary metabolite in the substrate file (value in parentheses indicates which model file); Sec Met, included as the secondary metabolite in the substrate file (value in parentheses indicates which model file); SF, scaling factor; Sub, included as substrate in file (value in parentheses indicates which model file); t1/2, half‐life; Tmax, time to maximum plasma concentration.; UGT1A3, urine diphosphate glucuronosyltransferase 1B3; Vdss, steady‐state volume of distribution; Vmax, mamimal rate of metabolism.
Change made for incorporation into lactone model file (file 2).
Assumed to be similar to parent when data not available.
Optimized as explained in MethodsMethods2.