TABLE 3.
Physiological and kinetic default values used in PBPK model and probability distributions applied for uncertainty and sensitivity analyses.
| Physiological parameters | Abbreviation | Default value | Distribution |
|---|---|---|---|
| Body weight (kg) | BW | 72.3 | N a (72.3, 9.05) |
| % BW | |||
| Total vascularised tissues | VT | 0.95 | - |
| Liver | VLiC | 3.09 | N(3.09, 0.8) |
| Kidney | VKic | 0.58 | N(0.58, 0.15) |
| Fat | VFaC | 19.5 | LN(3.42, 0.43) |
| Gut | VGuC | 1.50 | N(1.5, 0.2) |
| Stomach | VStC | 0.22 | N(0.22, 0.07) |
| Slowly perfused tissue | VSpdC | 60.7 | N(60.7, 9.4) |
| Rapidly perfused tissue | VRpdC | 3.71 | N(3.7, 0.26) |
| Blood | VBldC | 5.0 | N(5.0, 1.0) |
| Cardiac output (L h-1 kg-1 BW) | QCC | 14 | N(13.8, 2.5) |
| % Cardiac output | |||
| Liver | QHepartC | 6.9 | N(6.9, 0.5) |
| Kidney | QKiC | 20 | N(20.0, 3.0) |
| Fat | QFaC | 5.0 | N(5.3, 0.3) |
| Gut | QGuC | 14.9 | N(14.9, 3.0) |
| Stomach | QStC | 1.1 | N(1.1, 0.1) |
| Slowly perfused tissue | QSpdC | 28.7 | N(28.7, 1.9) |
| Rapidly perfused tissue | QRpdC | 23.0 | N(23.0, 2.8) |
| Metabolic Clearance (minutes) | |||
| In vitro half-life DPHP | T½DPHP | 3 b | HN(10) |
| In vitro half-life MPHP | T½MPHP | 8.05 | N(8.05, 4.0) |
| In vivo DPHP gut half-life | T½DPHP_gut | 60 c | N(30, 10) |
| Protein Binding (%) | |||
| DPHP | FB_DPHP | 99.75 | U(0.95, 1.00) |
| MPHP | FB_MPHP | 98.54 | U(0.90, 1.00) |
| Elimination (liver to bile) (h-1) | |||
| DPHP | k1_DPHP_liver | 10 | HN(10) |
| Microsomal protein yield (mg g-1) | |||
| Hepatic | MPY | 34 d | N(34, 10) |
| Gut | MPYgut | 3.9 e | N(3.9, 2.0) |
| Parameters | Abbreviation | Default value | Distribution |
|---|---|---|---|
| Blood:tissue partition coefficients | |||
| DPHP | |||
| Plasma | Pbab | 15.5 | U(1, 30) |
| Adipose | Pfab | 63.4 | U(32, 125) |
| Liver | Plib | 5.89 | U(1, 50) |
| Kidney | Pkib | 5.89 | U(3, 12) |
| Red blood cells | Prbcb | 3.29 | U(3, 12) |
| Gut | Pgub | 7.4 | U(1, 50) |
| Stomach | Pstb | 3.7 | U(2, 8) |
| Rapidly Perfused | Prpdb | 3.7 | U(2, 8) |
| Slowly Perfused | Pspdb | 3.29 | U(2, 8) |
| MPHP | |||
| Plasma | PbaM | 25.23 | U(1, 50) |
| Adipose | PfaM | 29.10 | U(15, 60) |
| Liver | PliM | 54.8 | U(1, 30) |
| Kidney | PkiM | 15.5 | U(1, 30) |
| Red blood cells | PrbcM | 6.67 | U(3, 12) |
| Gut | PguM | 25.2 | U(1, 30) |
| Stomach | PstM | 25.2 | U(12, 50) |
| Rapidly Perfused | PrpdM | 12.20 | U(6, 24) |
| Slowly Perfused | PspdM | 7.51 | U(4, 15) |
| Gastric emptying (h-1) f | |||
| Maximum | k(max) | 10.2 | U(5.1, 20.4) |
| Minimum | k(min) | 0.005 | U(0.0025, 0.01) |
| Absorption (fraction of dose) | |||
| Fraction of dose taken up into liver | FRACDOSEHep | 0.1 | U(0.001, 0.4) |
| Fraction of dose taken up into lymph | FRACDOSELymph | 0.5 | U(0.001, 0.15) |
| Absorption (h-1) | |||
| Gut | kGa | 25.1 | U(12.55, 50.2) |
| Absorption in Stomach | BELLYPERM | 0.685 | U(0.05, 7.5) |
| Absorption in first GI Tract compartment | GIPERM1 | 5.1 | U(0.05, 10) |
| Absorption in first GI Tract compartment | GIPERM2 | 5.1 | U(0.05, 30) |
| Absorption in Lymph via stomach | BELLYPERMLymph | 0.685 | U(0.34, 0.99) |
| Absorption in Lymph via GI Tract | GIPERMLymph | 5.1 | U(2.6, 7.6) |
| Absorption into blood from lymph | K1Lymph | 0.2 | U(0.05, 3) |
| Delays (h-1) | |||
| Transportation delay in gut | Gutlag | 1 | U(0.01, 5) |
| Delay associated with lymphatic uptake | LymphLag | 1 | (0.01, 7) |
| Fraction unavailable for first pass metabolism (fraction of dose) | |||
| MPHP in gut | EscapeFracgut | 0.5 | U(0, 1) |
| MPHP in liver | EscapeFracliver | 0.5 | U(0, 1) |
| Metabolism of MPHP (fractions) | |||
| Fraction of MPHP to OH-MPHP | FracMetabOH | 0.3 | U(0.2, 0.5) |
| Fraction of MPHP to cx-MPHP | FracMetabcx | 0.02 | U(0.01, 0.05) |
| Urinary elimination rate (h-1) | |||
| 5OH-MEHA | K1_MOH | 1 | U(0.01, 5) |
| 5cx-MEPA | K1_5cx | 1 | U(0.01, 5) |
a
Distributions, N, normal; LN, Lognormal; HN, Half normal; U, uniform.
b
Estimated.
c
Estimated.
d
Barter et al. (2007), Howgate et al. (2006)
e
Pacifici, et al. (1988), Soars, et al. (2002)
f
Loizou and Spendiff (2004)