parameterize_pbtk: Parameters for a generic physiologically-based toxicokinetic...

In httk: High-Throughput Toxicokinetics

Parameters for a generic physiologically-based toxicokinetic model

Description

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.

Usage

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,
  million.cells.per.gliver = 110,
  liver.density = 1.05,
  kgutabs = NA,
  Caco2.options = NULL
)

Arguments

chem.cas	Chemical Abstract Services Registry Number (CAS-RN) – the chemical must be identified by either CAS, name, or DTXISD
chem.name	Chemical name (spaces and capitalization ignored) – the chemical must be identified by either CAS, name, or DTXISD
dtxsid	EPA's 'DSSTox Structure ID (https://comptox.epa.gov/dashboard) – the chemical must be identified by either CAS, name, or DTXSIDs
species	Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human").
default.to.human	Substitutes missing animal values with human values if true (hepatic intrinsic clearance or fraction of unbound plasma).
tissuelist	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.
force.human.clint.fup	Forces use of human values for hepatic intrinsic clearance and fraction of unbound plasma if true.
clint.pvalue.threshold	Hepatic clearance for chemicals where the in vitro clearance assay result has a p-values greater than the threshold are set to zero.
adjusted.Funbound.plasma	Uses Pearce et al. (2017) lipid binding adjustment for Funbound.plasma (which impacts partition coefficients) when set to TRUE (Default).
adjusted.Clint	Uses Kilford et al. (2008) hepatocyte incubation binding adjustment for Clint when set to TRUE (Default).
regression	Whether or not to use the regressions in calculating partition coefficients.
suppress.messages	Whether or not the output message is suppressed.
restrictive.clearance	In calculating hepatic.bioavailability, protein binding is not taken into account (set to 1) in liver clearance if FALSE.
minimum.Funbound.plasma	f_{up} is not allowed to drop below this value (default is 0.0001).
class.exclude	Exclude chemical classes identified as outside of domain of applicability by relevant modelinfo_[MODEL] file (default TRUE).
million.cells.per.gliver	Hepatocellularity (defaults to 110 10^6 cells/g-liver, from Carlile et al. (1997))
liver.density	Liver density (defaults to 1.05 g/mL from International Commission on Radiological Protection (1975))
kgutabs	Oral absorption rate from gut (determined from Peff)
Caco2.options	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.

Details

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 F_bio=F_abs*F_gut*F_hep. Only if F_bio has been measured in vivo and is found in table chem.physical_and_invitro.data then we set F_abs*F_gut to the measured value divided by F_hep where F_hep is estimated from in vitro TK data using calc_hep_bioavailability. If Caco2 membrane permeability data or predictions are available F_abs is estimated using calc_fabs.oral. Intrinsic hepatic metabolism is used to very roughly estimate F_gut using calc_fgut.oral.

Value

BW	Body Weight, kg.
Clmetabolismc	Hepatic Clearance, L/h/kg BW.
Fabsgut	Fraction of the oral dose absorbed, i.e. the fraction of the dose that enters the gutlumen.
Funbound.plasma	Fraction of plasma that is not bound.
Fhep.assay.correction	The fraction of chemical unbound in hepatocyte assay using the method of Kilford et al. (2008)
hematocrit	Percent volume of red blood cells in the blood.
Kgut2pu	Ratio of concentration of chemical in gut tissue to unbound concentration in plasma.
kgutabs	Rate that chemical enters the gut from gutlumen, 1/h.
Kkidney2pu	Ratio of concentration of chemical in kidney tissue to unbound concentration in plasma.
Kliver2pu	Ratio of concentration of chemical in liver tissue to unbound concentration in plasma.
Klung2pu	Ratio of concentration of chemical in lung tissue to unbound concentration in plasma.
Krbc2pu	Ratio of concentration of chemical in red blood cells to unbound concentration in plasma.
Krest2pu	Ratio of concentration of chemical in rest of body tissue to unbound concentration in plasma.
million.cells.per.gliver	Millions cells per gram of liver tissue.
MW	Molecular Weight, g/mol.
Qcardiacc	Cardiac Output, L/h/kg BW^3/4.
Qgfrc	Glomerular Filtration Rate, L/h/kg BW^3/4, volume of fluid filtered from kidney and excreted.
Qgutf	Fraction of cardiac output flowing to the gut.
Qkidneyf	Fraction of cardiac output flowing to the kidneys.
Qliverf	Fraction of cardiac output flowing to the liver.
Rblood2plasma	The ratio of the concentration of the chemical in the blood to the concentration in the plasma from available_rblood2plasma.
Vartc	Volume of the arteries per kg body weight, L/kg BW.
Vgutc	Volume of the gut per kg body weight, L/kg BW.
Vkidneyc	Volume of the kidneys per kg body weight, L/kg BW.
Vliverc	Volume of the liver per kg body weight, L/kg BW.
Vlungc	Volume of the lungs per kg body weight, L/kg BW.
Vrestc	Volume of the rest of the body per kg body weight, L/kg BW.
Vvenc	Volume of the veins per kg body weight, L/kg BW.

Author(s)

John Wambaugh and Robert Pearce

References

\insertRef

pearce2017httkhttk

\insertRef

schmitt2008generalhttk

\insertRef

pearce2017evaluationhttk

\insertRef

kilford2008hepatocellularhttk

International Commission on Radiological Protection. Report of the task group on reference man. Vol. 23. Pergamon, Oxford. 1975.

See Also

solve_pbtk

calc_analytic_css_pbtk

predict_partitioning_schmitt

apply_clint_adjustment

tissue.data

physiology.data

Examples

 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) 

httk documentation built on Sept. 11, 2024, 9:32 p.m.