R Under development (unstable) (2024-12-19 r87451 ucrt) -- "Unsuffered Consequences"
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> # R CMD BATCH --no-timing --no-restore --no-save caco2_test.R caco2_test.Rout
> 
> # Get rid of anything in the workspace:
> rm(list=ls()) 
> 
> library(httk)
>                   
> p <- parameterize_pbtk(chem.cas="80-05-7")
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.
> print(p[["MW"]])
[1] 228.3
> print(p[["BW"]])
[1] 70
> print(p[["Fabsgut"]])
[1] 0.6441
> 
> # calculate what initial dose of 1 mg/kg should be in uM in the gut:
> initial.dose <- signif(1/1e3*1e6/p[["MW"]]*p[["BW"]]*p[["Fabsgut"]],
+                        4)
> # This should be the same as what solve_pbtk givesus:
> initial.dose == solve_pbtk(chem.cas="80-05-7",days=1)[1,"Agutlumen"]
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: Agutlumen, Atubules, Ametabolized
	uM: Cgut, Cliver, Cven, Clung, Cart, Crest, Ckidney, Cplasma
	uM*days: AUC

Agutlumen 
     TRUE 
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.
> 
>                   
> # By default we now include calculation of Fabs and Fgut (always had Fhep):
> calc_analytic_css(chem.name="bisphenol a",
+                   model="pbtk")
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.
> # Therefore if we set Fabs = Fgut = 1 with keetit100=TRUE, we should get a
> # higher predicted plasma steady-state concentration:
> calc_analytic_css(chem.name="bisphenol a",
+                   model="pbtk",
+                   Caco2.options=list(keepit100=TRUE))
Plasma concentration returned in uM units.
[1] 1.462
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.
> 
> # By default we now include calculation of Fabs and Fgut (we explicitly model
> # first-pass hepatic metabolism in the model "pbtk")
> head(solve_pbtk(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: Agutlumen, Atubules, Ametabolized
	uM: Cgut, Cliver, Cven, Clung, Cart, Crest, Ckidney, Cplasma
	uM*days: AUC

       time Agutlumen    Cgut    Cliver     Cven  Clung    Cart    Crest
[1,] 0.0000     197.5  0.0000  0.000000 0.000000 0.0000 0.00000 0.000000
[2,] 0.0001     197.3  0.1582  0.000479 0.000001 0.0000 0.00000 0.000000
[3,] 0.0104     180.0 10.1300  3.063000 0.036390 0.2967 0.03130 0.007976
[4,] 0.0208     164.1 13.6200  7.596000 0.102500 0.8846 0.09679 0.056220
[5,] 0.0312     149.6 14.7600 11.110000 0.162000 1.4230 0.15740 0.149600
[6,] 0.0416     136.3 14.9800 13.380000 0.206900 1.8320 0.20360 0.275500
     Ckidney  Cplasma Atubules Ametabolized      AUC
[1,]  0.0000 0.000000 0.000000     0.000000 0.000000
[2,]  0.0000 0.000001 0.000000     0.000000 0.000000
[3,]  0.3831 0.045780 0.000583     0.003302 0.000170
[4,]  1.7530 0.128900 0.004221     0.018490 0.001074
[5,]  3.2900 0.203700 0.011570     0.045260 0.002818
[6,]  4.5510 0.260300 0.021980     0.080160 0.005247
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.
> # Therefore if we set Fabs = Fgut = 1 with keetit100=TRUE, we should get a
> # higher tissue concentrations:
> head(solve_pbtk(chem.cas="80-05-7",days=1,
+                 Caco2.options=list(keepit100=TRUE)))
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: Agutlumen, Atubules, Ametabolized
	uM: Cgut, Cliver, Cven, Clung, Cart, Crest, Ckidney, Cplasma
	uM*days: AUC

       time Agutlumen  Cgut    Cliver     Cven    Clung   Cart   Crest Ckidney
[1,] 0.0000    306.60  0.00  0.000000 0.000000 0.000000 0.0000 0.00000   0.000
[2,] 0.0001    305.00  1.44  0.004367 0.000005 0.000002 0.0000 0.00000   0.000
[3,] 0.0104    177.90 72.10 23.760000 0.285200 2.344000 0.2485 0.06568   3.123
[4,] 0.0208    103.30 73.24 49.150000 0.678500 5.911000 0.6502 0.41250  12.340
[5,] 0.0312     59.93 59.47 59.110000 0.896400 7.952000 0.8846 0.97640  19.620
[6,] 0.0416     34.78 45.57 58.000000 0.954400 8.533000 0.9537 1.60100  22.760
      Cplasma Atubules Ametabolized      AUC
[1,] 0.000000 0.000000      0.00000 0.000000
[2,] 0.000006 0.000000      0.00000 0.000000
[3,] 0.358800 0.004803      0.02682 0.001386
[4,] 0.853500 0.031050      0.13340 0.007826
[5,] 1.128000 0.075960      0.28980 0.018340
[6,] 1.201000 0.129300      0.45730 0.030580
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.
> 
> # Reduce the number of samples used by Monte Carlo to decrease runtime for
> # CRAN checks (never use predictions with only ten draws):
> NSAMP <- 10
> 
> set.seed(1234)
> # Let's make sure that the monte carlo Css is also lower when some chemical
> # is not absorbed:
> Css1.caco <- calc_mc_css(chem.cas="15972-60-8",
+             model="3compartment",
+             samples=NSAMP)
Human plasma concentration returned in mg/L units for 0.95 quantile.
Warning messages:
1: In calc_ma(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Membrane affintity (MA) predicted with method of Yun and Edginton (2013), see calc_ma.
2: In available_rblood2plasma(chem.cas = chem.cas, species = species,  :
  Human in vivo measured Rblood2plasma used.
3: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
4: In (function (chem.name = NULL, chem.cas = NULL, dtxsid = NULL,  :
  calc_analytic_css deprecated argument daily.dose replaced with new argument dose, value given assigned to dose
> # The monte carlo Css should be higher with keepit100-TRUE
> set.seed(1234)
> Css1.100 <- calc_mc_css(chem.cas="15972-60-8",
+             model="3compartment",
+             samples=NSAMP,
+             Caco2.options=list(keepit100=TRUE))
Human plasma concentration returned in mg/L units for 0.95 quantile.
Warning messages:
1: In calc_ma(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Membrane affintity (MA) predicted with method of Yun and Edginton (2013), see calc_ma.
2: In available_rblood2plasma(chem.cas = chem.cas, species = species,  :
  Human in vivo measured Rblood2plasma used.
3: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Default value of 1.6 used for Caco2 permeability.
4: In (function (chem.name = NULL, chem.cas = NULL, dtxsid = NULL,  :
  calc_analytic_css deprecated argument daily.dose replaced with new argument dose, value given assigned to dose
> Css1.caco < Css1.100
 95% 
TRUE 
> 
> set.seed(1234)
> Css2.caco <- calc_mc_css(dtxsid="DTXSID6034392",
+                          samples=NSAMP,
+                          which.quantile=0.5)
Human plasma concentration returned in mg/L units for 0.5 quantile.
Warning messages:
1: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Clint is provided as a distribution.
2: In (function (chem.name = NULL, chem.cas = NULL, dtxsid = NULL,  :
  calc_analytic_css deprecated argument daily.dose replaced with new argument dose, value given assigned to dose
> set.seed(1234)
> Css2.100 <- calc_mc_css(dtxsid="DTXSID6034392",
+                         samples=NSAMP,
+                         Caco2.options = list(keepit100=TRUE),
+                         which.quantile=0.5)
Human plasma concentration returned in mg/L units for 0.5 quantile.
Warning messages:
1: In get_caco2(chem.cas = chem.cas, chem.name = chem.name, dtxsid = dtxsid,  :
  Clint is provided as a distribution.
2: In (function (chem.name = NULL, chem.cas = NULL, dtxsid = NULL,  :
  calc_analytic_css deprecated argument daily.dose replaced with new argument dose, value given assigned to dose
> Css2.caco < Css2.100
 50% 
TRUE 
> 
> quit("no")
> proc.time()
   user  system elapsed 
  12.04    0.45   12.45