Andersen et al Supplemental File S-2

Supplemental File S-2: In order this file has the PBPK model schematic, model parameters and model code.





Supplemental File S-2: Model Parameters for mouse DCM PBPK model. Label MOLWT BW QPC QCC Tissue Blood Flows (Fraction cardiac output) QLC QFC QRC QSC Partition Coefficients PB PF PL PR PS Metabolism Constants VMAXC

Value 85 0.025 29 16.5

Description

0.24 0.05 0.52 0.19

Molecular Weight Body Weight (kg) Pulmonary Ventilation (L/hr/ kg0.75) CARDIAC FLOW (L/hr/ kg0.75) Liver Fat Rapidly Perfused Poorly Perfused

23 4.5 1.6 0.52 0.44

Blood:Air Fat Liver Rapidly Perfused Slowly Perfused

13.0

Maximum Velocity Metabolism (mg/hr/ kg0.75)

KM 0.182 Affinity Constant Metabolism (mg/L) KFC 1.5 First Order Rate Constant (hr-1/kg0.25) Tissue Volumes (fraction of BW) VBL2C 7.60E-02 Blood VLUC 0.0038 Lung VFC 0.1 Fat VLC 0.04 Liver VRC 0.05 Rapidly Perfused VSC 0.72 Slowly Perfused Fraction of Tissue Volume that is lipid (Rat values for tissue lipid fraction taken from Ruark et al. 2014) VLULC 7.00E-02 Lung VFLC 0.855 Fat VLLC 0.06 Liver VRLC 4.40E-02 Rapidly perfused VSLC 0.019 Slowly perfused PAFACTOR 10 Reduction of Cardiac output for deep tissue (Unitless)

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CarboxyHemoglobin Constants DLC RENCOC VWC KEC ABCOC MW L12D M O2 HBTOT PAIR RHO SOL MBR

0.06 0.035 0.34 0.007 0.117 28 1.25 95 0.13 10 713 1102 0.03 159

Diffusion Coefficient of Lung (L/hr/mm Hg/ kg0.92) Endogenous Production Rate CO (mg/hr/ kg0.75) Volume H2O Available to BR (L/kg) BR EXCRETION CONST (hr-1/kg) Amount Background CO (mg/kg) CO Molecular Weight L12=28/MOLWT/L12D: Reduces CO Yield Haldane Coefficient 4.16/32 mols/L moles/L mm Hg mg/L mg/L/mm Hg 2 Br in BRBRME





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Supplemental File S-2; acslX™ Code for PBPK model for DCM in the mouse model including a CO submodel PROGRAM ! DCM model for mouse including CO submodel (J. Campbell 2016) INITIAL CONSTANT DLC = .060 !!DIF. COEF OF LUNG (L/HR/MM HG/KG)! CONSTANT RENCOC = .035 !!RATE OF ENDOGENOUS CO PROD (MG/HR/KG)! CONSTANT VBL2C = .076 !!VOLUME OF BLOOD (L/KG)! CONSTANT QPC = 29. !!PULMONARY FLOW (L/HR/KG)! CONSTANT QCC = 16.5 !!CARDIAC FLOW (L/HR/KG)! CONSTANT VWC = 0.34 !!VOL H2O AVAIL TO BR (L/KG)! CONSTANT KEC = .007 !!BR EXCRETION CONST (HR-1/KG)! CONSTANT ABCOC = .117 !!AMT BACKGROUND CO (MG/KG)! CONSTANT MW = 28. !!CO MOL WT! CONSTANT L12D = 1.25 !!L12=28/MOLWT/L12D:REDUCES CO YIELD! CONSTANT M = 95. !!HALDANE COEFFICIENT! CONSTANT O2 = .13 !!=4.16/32 M MOLES/L! CONSTANT HBTOT = 10. !!M MOLES/L! CONSTANT PAIR = 713. !!MM HG! CONSTANT RHO = 1102. !!MG/L! CONSTANT SOL = 0.03 !!MG/L/MM HG! CONSTANT BW = 0.025 !!BODY WT (KG)! CONSTANT MOLWT = 85. !!METHYLENE CHLORIDE MOL WT! CONSTANT PL = 1.6 !!LIVER/BLOOD PART COEF! CONSTANT PF = 4.5 !!FAT/BLOOD PART COEF! CONSTANT PS = .44 !!MUSCLE/BLOOD PART COEF! CONSTANT PR = .52 !!LIVER/BLOOD PART COEF! CONSTANT PB = 23. !!BLOOD/AIR PART COEF! CONSTANT VMAXC = 13. !!MAXIMUM REACTION RATE (MG/KG/HR)! CONSTANT KM = 1.0 !!MICHALIS CONSTANT (MG/L)! CONSTANT MBR = 159. !!2 BR IN BRBRME! CONSTANT KFC = 1.5 !!FIRST ORDER RATE CONST (HR-1/KG)! CONSTANT VFC = .10 !!PERCENT BODY FAT! CONSTANT VSC = .72 !!PERCENT BODY MUSCLE!

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CONSTANT VLC = .04 !!PERCENT OF BODY WT! CONSTANT VRC = .05 !!PERCENT BODY ORGANS! CONSTANT FF = 1.21 CONSTANT CCONC = 0. !!CHAMBER INITIAL CONCENTRATION (MG/L)! CONSTANT QLC = 0.24 CONSTANT QFC = 0.05 CONSTANT QRC = 0.52 CONSTANT QSC = 0.19 CONSTANT NRATS = 1 CONSTANT VCHC = 2.6 CONSTANT KLC = 0.0 CONSTANT KLCOC = 0.48 CONSTANT CCO = 0. CONSTANT DOSEMAX = 23.0 !will expose for one day if