Generate a chemical- and species-specific set of PBPK model parameters.
Parameters include
tissue:plasma partition coefficients, organ volumes, and flows
for the tissue lumping scheme specified by argument tissuelist.
Tissure:(fraction unbound in) plasma partitition coefficients are predicted
via Schmitt (2008)'s method as modified by Pearce et al. (2017) using
predict_partitioning_schmitt. Organ volumes and flows are
retrieved from table physiology.data.
Tissues must be described in table tissue.data.
parameterize_pbtk(
chem.cas = NULL,
chem.name = NULL,
dtxsid = NULL,
species = "Human",
default.to.human = FALSE,
tissuelist = list(liver = c("liver"), kidney = c("kidney"), lung = c("lung"), gut =
c("gut")),
force.human.clint.fup = FALSE,
clint.pvalue.threshold = 0.05,
adjusted.Funbound.plasma = TRUE,
adjusted.Clint = TRUE,
regression = TRUE,
suppress.messages = FALSE,
restrictive.clearance = TRUE,
minimum.Funbound.plasma = 1e-04,
class.exclude = TRUE,
physchem.exclude = TRUE,
million.cells.per.gliver = 110,
liver.density = 1.05,
kgutabs = NA,
Caco2.options = NULL,
...
)Body Weight, kg.
Hepatic Clearance, L/h/kg BW.
Fraction of the oral dose absorbed, i.e. the fraction of the dose that enters the gutlumen.
Fraction of plasma that is not bound.
The fraction of chemical unbound in hepatocyte assay using the method of Kilford et al. (2008)
Percent volume of red blood cells in the blood.
Ratio of concentration of chemical in gut tissue to unbound concentration in plasma.
Rate that chemical enters the gut from gutlumen, 1/h.
Ratio of concentration of chemical in kidney tissue to unbound concentration in plasma.
Ratio of concentration of chemical in liver tissue to unbound concentration in plasma.
Ratio of concentration of chemical in lung tissue to unbound concentration in plasma.
Ratio of concentration of chemical in red blood cells to unbound concentration in plasma.
Ratio of concentration of chemical in rest of body tissue to unbound concentration in plasma.
Millions cells per gram of liver tissue.
Molecular Weight, g/mol.
Cardiac Output, L/h/kg BW^3/4.
Glomerular Filtration Rate, L/h/kg BW^3/4, volume of fluid filtered from kidney and excreted.
Fraction of cardiac output flowing to the gut.
Fraction of cardiac output flowing to the kidneys.
Fraction of cardiac output flowing to the liver.
The ratio of the concentration of the chemical in the blood to the concentration in the plasma from available_rblood2plasma.
Volume of the arteries per kg body weight, L/kg BW.
Volume of the gut per kg body weight, L/kg BW.
Volume of the kidneys per kg body weight, L/kg BW.
Volume of the liver per kg body weight, L/kg BW.
Volume of the lungs per kg body weight, L/kg BW.
Volume of the rest of the body per kg body weight, L/kg BW.
Volume of the veins per kg body weight, L/kg BW.
Chemical Abstract Services Registry Number (CAS-RN) -- the chemical must be identified by either CAS, name, or DTXISD
Chemical name (spaces and capitalization ignored) -- the chemical must be identified by either CAS, name, or DTXISD
EPA's 'DSSTox Structure ID (https://comptox.epa.gov/dashboard) -- the chemical must be identified by either CAS, name, or DTXSIDs
Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human").
Substitutes missing animal values with human values if true (hepatic intrinsic clearance or fraction of unbound plasma).
Specifies compartment names and tissues groupings.
Remaining tissues in tissue.data are lumped in the rest of the body.
However, solve_pbtk only works with the default parameters.
Forces use of human values for hepatic intrinsic clearance and fraction of unbound plasma if true.
Hepatic clearance for chemicals where the in vitro clearance assay result has a p-values greater than the threshold are set to zero.
Uses Pearce et al. (2017) lipid binding adjustment for Funbound.plasma (which impacts partition coefficients) when set to TRUE (Default).
Uses Kilford et al. (2008) hepatocyte incubation binding adjustment for Clint when set to TRUE (Default).
Whether or not to use the regressions in calculating partition coefficients.
Whether or not the output message is suppressed.
In calculating hepatic.bioavailability, protein binding is not taken into account (set to 1) in liver clearance if FALSE.
\(f_{up}\) is not allowed to drop below this value (default is 0.0001).
Exclude chemical classes identified as outside of domain of applicability by relevant modelinfo_[MODEL] file (default TRUE).
Exclude chemicals on the basis of physico-chemical properties (currently only Henry's law constant) as specified by the relevant modelinfo_[MODEL] file (default TRUE).
Hepatocellularity (defaults to 110 10^6 cells/g-liver, from Carlile et al. (1997))
Liver density (defaults to 1.05 g/mL from International Commission on Radiological Protection (1975))
Oral absorption rate from gut (determined from Peff)
A list of options to use when working with Caco2 apical to
basolateral data Caco2.Pab, default is Caco2.options = list(Caco2.Pab.default = 1.6,
Caco2.Fabs = TRUE, Caco2.Fgut = TRUE, overwrite.invivo = FALSE, keepit100 = FALSE). Caco2.Pab.default sets the default value for
Caco2.Pab if Caco2.Pab is unavailable. Caco2.Fabs = TRUE uses Caco2.Pab to calculate
fabs.oral, otherwise fabs.oral = Fabs. Caco2.Fgut = TRUE uses Caco2.Pab to calculate
fgut.oral, otherwise fgut.oral = Fgut. overwrite.invivo = TRUE overwrites Fabs and Fgut in vivo values from literature with
Caco2 derived values if available. keepit100 = TRUE overwrites Fabs and Fgut with 1 (i.e. 100 percent) regardless of other settings.
See get_fbio for further details.
Additional arguments, not currently used.
John Wambaugh and Robert Pearce
By default, this function initializes the parameters needed in the functions
solve_pbtk, calc_css, and others using the httk
default generic PBTK model (for oral and intravenous dosing only).
The default PBTK model includes an explicit first pass of the chemical through
the liver before it becomes available to systemic blood. We model systemic oral bioavailability as
Fbio=Fabs*Fgut*Fhep.
Only if Fbio
has been measured in vivo and is found in
table chem.physical_and_invitro.data then we set
Fabs*Fgut
to the measured value divided by
Fhep
where Fhep
is estimated from in vitro TK data using
calc_hep_bioavailability.
If Caco2 membrane permeability data or predictions
are available Fabs is estimated
using calc_fabs.oral.
Intrinsic hepatic metabolism is used to very roughly estimate
Fgut
using calc_fgut.oral.
pearce2017httkhttk
schmitt2008generalhttk
pearce2017evaluationhttk
kilford2008hepatocellularhttk
International Commission on Radiological Protection. Report of the task group on reference man. Vol. 23. Pergamon, Oxford. 1975.
solve_pbtk
calc_analytic_css_pbtk
predict_partitioning_schmitt
apply_clint_adjustment
tissue.data
physiology.data
parameters <- parameterize_pbtk(chem.cas='80-05-7')
parameters <- parameterize_pbtk(chem.name='Bisphenol-A',species='Rat')
# Change the tissue lumping (note, these model parameters will not work with our current solver):
compartments <- list(liver=c("liver"),fast=c("heart","brain","muscle","kidney"),
lung=c("lung"),gut=c("gut"),slow=c("bone"))
parameterize_pbtk(chem.name="Bisphenol a",species="Rat",default.to.human=TRUE,
tissuelist=compartments)
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