R Under development (unstable) (2024-09-03 r87093 ucrt) -- "Unsuffered Consequences" Copyright (C) 2024 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] 0.9417 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] 0.9417 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] 0.9417 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] 253.6 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] 5.496 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",days=1)) 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, Cplasma uM*days: AUC time Aintestine Cliver Csyscomp Cplasma Atubules Ametabolized [1,] 0.00000000 197.5 0.0000000 0.000e+00 0.000e+00 0.0000000 0.000e+00 [2,] 0.00010000 197.3 0.0003165 4.700e-08 5.900e-08 0.0000000 2.749e-06 [3,] 0.01041667 180.0 0.3149000 7.419e-03 9.334e-03 0.0001418 4.420e-01 [4,] 0.02083333 164.0 0.4776000 2.530e-02 3.183e-02 0.0010500 1.534e+00 [5,] 0.03125000 149.5 0.5469000 4.732e-02 5.953e-02 0.0031240 2.923e+00 [6,] 0.04166667 136.3 0.5692000 7.027e-02 8.840e-02 0.0065000 4.428e+00 AUC [1,] 0.000e+00 [2,] 0.000e+00 [3,] 2.573e-05 [4,] 1.905e-04 [5,] 5.669e-04 [6,] 1.179e-03 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",days=1)) 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, Cplasma uM*days: AUC time Aintestine Cliver Csyscomp Cplasma Atubules Ametabolized [1,] 0.00000000 197.5 0.0000000 0.000e+00 0.000e+00 0.0000000 0.000e+00 [2,] 0.00010000 197.3 0.0003165 4.700e-08 5.900e-08 0.0000000 2.749e-06 [3,] 0.01041667 180.0 0.3149000 7.419e-03 9.334e-03 0.0001418 4.420e-01 [4,] 0.02083333 164.0 0.4776000 2.530e-02 3.183e-02 0.0010500 1.534e+00 [5,] 0.03125000 149.5 0.5469000 4.732e-02 5.953e-02 0.0031240 2.923e+00 [6,] 0.04166667 136.3 0.5692000 7.027e-02 8.840e-02 0.0065000 4.428e+00 AUC [1,] 0.000e+00 [2,] 0.000e+00 [3,] 2.573e-05 [4,] 1.905e-04 [5,] 5.669e-04 [6,] 1.179e-03 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"),days=1)) 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, Cplasma uM*days: AUC time Aintestine Cliver Csyscomp Cplasma Atubules Ametabolized [1,] 0.00000000 197.5 0.0000000 0.000e+00 0.000e+00 0.0000000 0.000e+00 [2,] 0.00010000 197.3 0.0003165 4.700e-08 5.900e-08 0.0000000 2.749e-06 [3,] 0.01041667 180.0 0.3149000 7.419e-03 9.334e-03 0.0001418 4.420e-01 [4,] 0.02083333 164.0 0.4776000 2.530e-02 3.183e-02 0.0010500 1.534e+00 [5,] 0.03125000 149.5 0.5469000 4.732e-02 5.953e-02 0.0031240 2.923e+00 [6,] 0.04166667 136.3 0.5692000 7.027e-02 8.840e-02 0.0065000 4.428e+00 AUC [1,] 0.000e+00 [2,] 0.000e+00 [3,] 2.573e-05 [4,] 1.905e-04 [5,] 5.669e-04 [6,] 1.179e-03 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",days=2) 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, Cplasma 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] 197.5 > initial_default_dose_intestine = out_default_dosing[1,"Aintestine"] > head(initial_default_dose_intestine) Aintestine 197.5 > > out_nondefault_dosing = solve_3comp(chem.name = "bisphenol a", + daily.dose =3,doses.per.day = 5, + days=2) 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, Cplasma 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] 118.4003 > initial_nondefault_dose_intestine = out_nondefault_dosing[2,"Aintestine"] > head(initial_nondefault_dose_intestine) Aintestine 118.4 > > p <- parameterize_3comp(chem.name="Aminopterin")[sort(names(parameterize_3comp(chem.name="Aminopterin")))] There were 16 warnings (use warnings() to see them) > # Try to standardize order of variable names > for (this.param in names(p)[order(toupper(names(p)))]) cat(paste(this.param,": ",p[[this.param]],"\r\n",sep="")) BW: 70 Caco2.Pab: 1.6 Caco2.Pab.dist: NA Clint: 0 Clint.dist: NA Clmetabolismc: 0 Fabsgut: 0.6448 Fhep.assay.correction: 0.9561 Funbound.plasma: 0.747 Funbound.plasma.adjustment: 0.996 Funbound.plasma.dist: NA hematocrit: 0.44 Kgut2pu: 1.68 kgutabs: 0.3711 Kliver2pu: 3.803 Krbc2pu: 0.8576 Krest2pu: 0.9856 liver.density: 1.05 MA: 19 million.cells.per.gliver: 110 MW: 440.4 pKa_Accept: 8.09 pKa_Donor: 2.81 Pow: 0.8903 Qcardiacc: 13.88 Qgfrc: 0.3099 Qgutf: 0.2054 Qliverf: 0.0535 Rblood2plasma: 0.8419 Vgutc: 0.0158 Vliverc: 0.02448 Vrestc: 0.7879 > > quit("no") > proc.time() user system elapsed 14.93 0.39 15.26