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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")[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"))
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
[1,] 0.00000000     197.5  0.0000 0.000e+00 0.000e+00 0.000e+00 0.000e+00
[2,] 0.00010000     197.3  0.1582 4.792e-04 5.620e-07 3.220e-07 2.000e-09
[3,] 0.01041667     180.0 10.1400 3.070e+00 3.649e-02 2.976e-01 3.140e-02
[4,] 0.02083333     164.0 13.6300 7.610e+00 1.027e-01 8.865e-01 9.700e-02
[5,] 0.03125000     149.5 14.7600 1.113e+01 1.622e-01 1.425e+00 1.576e-01
[6,] 0.04166667     136.3 14.9800 1.339e+01 2.072e-01 1.834e+00 2.038e-01
        Crest Ckidney   Cplasma  Atubules Ametabolized       AUC
[1,] 0.000000  0.0000 0.000e+00 0.0000000    0.000e+00 0.0000000
[2,] 0.000000  0.0000 7.060e-07 0.0000000    5.000e-09 0.0000000
[3,] 0.008015  0.3847 4.590e-02 0.0005859    3.316e-03 0.0001704
[4,] 0.056450  1.7590 1.292e-01 0.0042390    1.856e-02 0.0010780
[5,] 0.150100  3.2970 2.041e-01 0.0116100    4.541e-02 0.0028280
[6,] 0.276300  4.5580 2.606e-01 0.0220600    8.041e-02 0.0052650
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",
+                 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
[1,] 0.00000000    306.60  0.00  0.000000 0.000e+00 0.000e+00 0.000e+00 0.00000
[2,] 0.00010000    305.00  1.44  0.004367 4.589e-06 1.974e-06 1.500e-08 0.00000
[3,] 0.01041667    177.80 72.13 23.810000 2.859e-01 2.350e+00 2.492e-01 0.06599
[4,] 0.02083333    103.10 73.21 49.210000 6.795e-01 5.920e+00 6.513e-01 0.41410
[5,] 0.03125000     59.77 59.40 59.130000 8.970e-01 7.958e+00 8.853e-01 0.97940
[6,] 0.04166667     34.66 45.48 57.970000 9.544e-01 8.533e+00 9.538e-01 1.60500
       Ckidney   Cplasma Atubules Ametabolized      AUC
[1,] 0.000e+00 0.000e+00 0.000000    0.000e+00 0.000000
[2,] 2.000e-09 5.773e-06 0.000000    4.000e-08 0.000000
[3,] 3.135e+00 3.597e-01 0.004826    2.693e-02 0.001392
[4,] 1.237e+01 8.548e-01 0.031170    1.338e-01 0.007854
[5,] 1.964e+01 1.129e+00 0.076200    2.906e-01 0.018390
[6,] 2.277e+01 1.201e+00 0.129600    4.583e-01 0.030660
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 
  15.96    0.48   16.43