R Under development (unstable) (2023-12-04 r85659 ucrt) -- "Unsuffered Consequences" Copyright (C) 2023 The R Foundation for Statistical Computing Platform: x86_64-w64-mingw32/x64 R is free software and comes with ABSOLUTELY NO WARRANTY. You are welcome to redistribute it under certain conditions. Type 'license()' or 'licence()' for distribution details. R is a collaborative project with many contributors. Type 'contributors()' for more information and 'citation()' on how to cite R or R packages in publications. Type 'demo()' for some demos, 'help()' for on-line help, or 'help.start()' for an HTML browser interface to help. Type 'q()' to quit R. > # R CMD BATCH --no-timing --no-restore --no-save 3comp_test.R 3comp_test.Rout > > # Get rid of anything in the workspace: > rm(list=ls()) > > library(httk) > > calc_analytic_css(chem.name="bisphenol a",model="3compartment") Plasma concentration returned in uM units. [1] 1.588 Warning messages: 1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Clint is provided as a distribution. 2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) : Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu. 3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Fraction unbound is provided as a distribution. 4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment, : Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction. 5: In available_rblood2plasma(chem.cas = chem.cas, species = species, : Human in vivo measured Rblood2plasma used. 6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid, : Default value of 1.6 used for Caco2 permeability. > calc_analytic_css(chem.cas="80-05-7",model="3compartment") Plasma concentration returned in uM units. [1] 1.588 Warning messages: 1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Clint is provided as a distribution. 2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) : Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu. 3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Fraction unbound is provided as a distribution. 4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment, : Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction. 5: In available_rblood2plasma(chem.cas = chem.cas, species = species, : Human in vivo measured Rblood2plasma used. 6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid, : Default value of 1.6 used for Caco2 permeability. > calc_analytic_css(parameters=parameterize_3comp(chem.cas="80-05-7"),model="3compartment") Plasma concentration returned in uM units. [1] 1.588 Warning messages: 1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Clint is provided as a distribution. 2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) : Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu. 3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Fraction unbound is provided as a distribution. 4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment, : Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction. 5: In available_rblood2plasma(chem.cas = chem.cas, species = species, : Human in vivo measured Rblood2plasma used. 6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid, : Default value of 1.6 used for Caco2 permeability. > calc_analytic_css(chem.name="bisphenol a",model="3compartment",tissue="liver") Plasma concentration for liver returned in uM units. [1] 28.5 Warning messages: 1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Clint is provided as a distribution. 2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) : Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu. 3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Fraction unbound is provided as a distribution. 4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment, : Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction. 5: In available_rblood2plasma(chem.cas = chem.cas, species = species, : Human in vivo measured Rblood2plasma used. 6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid, : Default value of 1.6 used for Caco2 permeability. > calc_analytic_css(chem.name="bisphenol a",model="3compartment",tissue="brain") Plasma concentration for brain returned in uM units. [1] 9.268 Warning messages: 1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Clint is provided as a distribution. 2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) : Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu. 3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Fraction unbound is provided as a distribution. 4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment, : Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction. 5: In available_rblood2plasma(chem.cas = chem.cas, species = species, : Human in vivo measured Rblood2plasma used. 6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid, : Default value of 1.6 used for Caco2 permeability. > > head(solve_3comp(chem.name="bisphenol a")) None of the monitored components undergo unit conversions (i.e. conversion factor of 1). AUC is area under the plasma concentration curve in uM*days units with Rblood2plasma = 0.795. The model outputs are provided in the following units: umol: Aintestine, Atubules, Ametabolized uM: Cliver, Csyscomp uM*days: AUC time Aintestine Cliver Csyscomp Atubules Ametabolized AUC [1,] 0.00000000 263.90 0.00 0.00000 0.000e+00 0.00000 0.000e+00 [2,] 0.00100000 250.40 5.70 0.01154 6.223e-06 0.02726 3.365e-06 [3,] 0.01041667 153.00 30.38 0.98590 7.379e-03 2.43900 3.990e-03 [4,] 0.02083333 88.72 26.68 2.21600 3.881e-02 5.84100 2.098e-02 [5,] 0.03125000 51.45 20.77 3.03100 8.999e-02 8.58800 4.866e-02 [6,] 0.04166667 29.83 16.70 3.51300 1.534e-01 10.75000 8.297e-02 Cplasma [1,] 0.00000 [2,] 0.01154 [3,] 0.98590 [4,] 2.21600 [5,] 3.03100 [6,] 3.51300 Warning messages: 1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Clint is provided as a distribution. 2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) : Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu. 3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Fraction unbound is provided as a distribution. 4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment, : Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction. 5: In available_rblood2plasma(chem.cas = chem.cas, species = species, : Human in vivo measured Rblood2plasma used. 6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid, : Default value of 1.6 used for Caco2 permeability. > head(solve_3comp(chem.cas="80-05-7")) None of the monitored components undergo unit conversions (i.e. conversion factor of 1). AUC is area under the plasma concentration curve in uM*days units with Rblood2plasma = 0.795. The model outputs are provided in the following units: umol: Aintestine, Atubules, Ametabolized uM: Cliver, Csyscomp uM*days: AUC time Aintestine Cliver Csyscomp Atubules Ametabolized AUC [1,] 0.00000000 263.90 0.00 0.00000 0.000e+00 0.00000 0.000e+00 [2,] 0.00100000 250.40 5.70 0.01154 6.223e-06 0.02726 3.365e-06 [3,] 0.01041667 153.00 30.38 0.98590 7.379e-03 2.43900 3.990e-03 [4,] 0.02083333 88.72 26.68 2.21600 3.881e-02 5.84100 2.098e-02 [5,] 0.03125000 51.45 20.77 3.03100 8.999e-02 8.58800 4.866e-02 [6,] 0.04166667 29.83 16.70 3.51300 1.534e-01 10.75000 8.297e-02 Cplasma [1,] 0.00000 [2,] 0.01154 [3,] 0.98590 [4,] 2.21600 [5,] 3.03100 [6,] 3.51300 Warning messages: 1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Clint is provided as a distribution. 2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) : Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu. 3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Fraction unbound is provided as a distribution. 4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment, : Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction. 5: In available_rblood2plasma(chem.cas = chem.cas, species = species, : Human in vivo measured Rblood2plasma used. 6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid, : Default value of 1.6 used for Caco2 permeability. > head(solve_3comp(parameters=parameterize_3comp(chem.cas="80-05-7"))) None of the monitored components undergo unit conversions (i.e. conversion factor of 1). AUC is area under the plasma concentration curve in uM*days units with Rblood2plasma = 0.795. The model outputs are provided in the following units: umol: Aintestine, Atubules, Ametabolized uM: Cliver, Csyscomp uM*days: AUC time Aintestine Cliver Csyscomp Atubules Ametabolized AUC [1,] 0.00000000 263.90 0.00 0.00000 0.000e+00 0.00000 0.000e+00 [2,] 0.00100000 250.40 5.70 0.01154 6.223e-06 0.02726 3.365e-06 [3,] 0.01041667 153.00 30.38 0.98590 7.379e-03 2.43900 3.990e-03 [4,] 0.02083333 88.72 26.68 2.21600 3.881e-02 5.84100 2.098e-02 [5,] 0.03125000 51.45 20.77 3.03100 8.999e-02 8.58800 4.866e-02 [6,] 0.04166667 29.83 16.70 3.51300 1.534e-01 10.75000 8.297e-02 Cplasma [1,] 0.00000 [2,] 0.01154 [3,] 0.98590 [4,] 2.21600 [5,] 3.03100 [6,] 3.51300 Warning messages: 1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Clint is provided as a distribution. 2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) : Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu. 3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Fraction unbound is provided as a distribution. 4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment, : Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction. 5: In available_rblood2plasma(chem.cas = chem.cas, species = species, : Human in vivo measured Rblood2plasma used. 6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid, : Default value of 1.6 used for Caco2 permeability. 7: In solve_model(chem.name = chem.name, chem.cas = chem.cas, dtxsid = dtxsid, : Rblood2plasma not recalculated. Set recalc.blood2plasma to TRUE if desired. 8: In solve_model(chem.name = chem.name, chem.cas = chem.cas, dtxsid = dtxsid, : Clearance not recalculated. Set recalc.clearance to TRUE if desired. > > #Test that the input daily.dose and doses.per.day are all that goes through, > #excluding any default dosing. We want any specified dosing to take the place > #of the default, not add to it. > > #first get BW param for 3 comp model: > BW = parameterize_3comp(chem.name = 'bisphenol a')[['BW']] Warning messages: 1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Clint is provided as a distribution. 2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) : Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu. 3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Fraction unbound is provided as a distribution. 4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment, : Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction. 5: In available_rblood2plasma(chem.cas = chem.cas, species = species, : Human in vivo measured Rblood2plasma used. 6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid, : Default value of 1.6 used for Caco2 permeability. > #and get MW of bisphenol a for checking units > MW = get_physchem_param(param = "MW",chem.name = "bisphenol a") > #record intended default dosing in solve_model when no other dosing specified: > default_initial_dose_target_unscaled = 1 #mg/kg BW > initial_default_dose_target = default_initial_dose_target_unscaled* + BW/(MW*10^-3) #factor of 10^-3 to convert > #from g/mol to mg/umol, yielding a dose target in umol > head(initial_default_dose_target) [1] 306.6141 > > out_default_dosing = solve_3comp(chem.name = "bisphenol a") None of the monitored components undergo unit conversions (i.e. conversion factor of 1). AUC is area under the plasma concentration curve in uM*days units with Rblood2plasma = 0.795. The model outputs are provided in the following units: umol: Aintestine, Atubules, Ametabolized uM: Cliver, Csyscomp uM*days: AUC Warning messages: 1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Clint is provided as a distribution. 2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) : Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu. 3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Fraction unbound is provided as a distribution. 4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment, : Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction. 5: In available_rblood2plasma(chem.cas = chem.cas, species = species, : Human in vivo measured Rblood2plasma used. 6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid, : Default value of 1.6 used for Caco2 permeability. > #The following two initial dose metrics should be the same, and the same as > #the initial_default_dose_target in turn. > initial_default_dose = sum(out_default_dosing[1,]) > head(initial_default_dose) [1] 263.9 > initial_default_dose_intestine = out_default_dosing[1,"Aintestine"] > head(initial_default_dose_intestine) Aintestine 263.9 > > out_nondefault_dosing = solve_3comp(chem.name = "bisphenol a", + daily.dose =3,doses.per.day = 5) None of the monitored components undergo unit conversions (i.e. conversion factor of 1). AUC is area under the plasma concentration curve in uM*days units with Rblood2plasma = 0.795. The model outputs are provided in the following units: umol: Aintestine, Atubules, Ametabolized uM: Cliver, Csyscomp uM*days: AUC Warning messages: 1: In get_clint(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Clint is provided as a distribution. 2: In apply_clint_adjustment(Clint.point, Fu_hep = Fu_hep, suppress.messages = suppress.messages) : Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu. 3: In get_fup(dtxsid = dtxsid, chem.name = chem.name, chem.cas = chem.cas, : Fraction unbound is provided as a distribution. 4: In apply_fup_adjustment(fup.point, fup.correction = fup.adjustment, : Fup adjusted for in vivo lipid partitioning (Pearce, 2017), see calc_fup_correction. 5: In available_rblood2plasma(chem.cas = chem.cas, species = species, : Human in vivo measured Rblood2plasma used. 6: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid, : Default value of 1.6 used for Caco2 permeability. > #so, the dose target of what should appear at time zero in the intestine is: > initial_nondefault_dose_target = 3/5*BW/(MW*10^-3) > head(initial_nondefault_dose_target) [1] 183.9685 > > #the following two dose metrics should also be the same: > initial_nondefault_dose = sum(out_nondefault_dosing[2,]) #Use second row because > #it looks like eventdata only gets registered in the output after time zero. > head(initial_nondefault_dose) [1] 153.7512 > initial_nondefault_dose_intestine = out_nondefault_dosing[2,"Aintestine"] > head(initial_nondefault_dose_intestine) Aintestine 150.3 > > p <- parameterize_3comp(chem.name="Aminopterin")[sort(names(parameterize_3comp(chem.name="Aminopterin")))] There were 16 warnings (use warnings() to see them) > for (this.param in names(p)) cat(paste(this.param,": ",p[[this.param]],"\n")) BW : 70 Caco2.Pab : 1.6 Caco2.Pab.dist : NA Clint : 0 Clint.dist : NA Clmetabolismc : 0 Fabsgut : 0.8719 Fhep.assay.correction : 0.9482 Funbound.plasma : 0.7498 Funbound.plasma.adjustment : 0.9998 Funbound.plasma.dist : NA Kgut2pu : 1.373 Kliver2pu : 3.221 Krbc2pu : 0.7415 Krest2pu : 0.778 MA : 7.082 MW : 440.4 Pow : 0.03467 Qcardiacc : 13.88 Qgfrc : 0.3099 Qgutf : 0.2054 Qliverf : 0.0535 Rblood2plasma : 0.8046 Vgutc : 0.0158 Vliverc : 0.02448 Vrestc : 0.7879 hematocrit : 0.44 kgutabs : 2.18 liver.density : 1.05 million.cells.per.gliver : 110 pKa_Accept : 8.09 pKa_Donor : 2.81 > > quit("no") > proc.time() user system elapsed 5.23 0.23 5.45