parameterize_steadystate: Parameters for a three-compartment toxicokinetic model at...

In httk: High-Throughput Toxicokinetics

Parameters for a three-compartment toxicokinetic model at steady-state

Description

This function initializes the parameters needed in the functions calc_mc_css, calc_mc_oral_equiv, and calc_analytic_css for the three compartment steady state model ('3compartmentss') as used in Rotroff et al. (2010), Wetmore et al. (2012), Wetmore et al. (2015), and elsewhere. By assuming that enough time has passed to reach steady-state, we eliminate the need for tissue-specific parititon coefficients because we assume all tissues have come to equilibrium with the unbound concentration in plasma. However, we still use chemical properties to predict the blood:plasma ratio for estimating first-pass hepatic metabolism for oral exposures.

Usage

parameterize_steadystate(
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  species = "Human",
  clint.pvalue.threshold = 0.05,
  default.to.human = FALSE,
  class.exclude = TRUE,
  force.human.clint.fup = FALSE,
  adjusted.Funbound.plasma = TRUE,
  adjusted.Clint = TRUE,
  restrictive.clearance = TRUE,
  fup.lod.default = 0.005,
  suppress.messages = FALSE,
  minimum.Funbound.plasma = 1e-04,
  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").
clint.pvalue.threshold	Hepatic clearances with clearance assays having p-values greater than the threshold are set to zero.
default.to.human	Substitutes missing species-specific values with human values if TRUE (default is FALSE).
class.exclude	Exclude chemical classes identified as outside of domain of applicability by relevant modelinfo_[MODEL] file (default TRUE).
force.human.clint.fup	Uses human hepatic intrinsic clearance and fraction of unbound plasma in calculation of partition coefficients for rats if true.
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).
restrictive.clearance	In calculating hepatic.bioavailability, protein binding is not taken into account (set to 1) in liver clearance if FALSE.
fup.lod.default	Default value used for fraction of unbound plasma for chemicals where measured value was below the limit of detection. Default value is 0.0005.
suppress.messages	Whether or not the output message is suppressed.
minimum.Funbound.plasma	Monte Carlo draws less than this value are set equal to this value (default is 0.0001 – half the lowest measured Fup in our dataset).
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.
...	Other parameters

Details

We model systemic oral bioavailability as F_bio=F_abs*F_gut*F_hep. F_hep is estimated from in vitro TK data using calc_hep_bioavailability. 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 Otherwise, 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

Clint	Hepatic Intrinsic Clearance, uL/min/10^6 cells.
Fabsgut	Fraction of the oral dose absorbed and surviving gut metabolism, that is, the fraction of the dose that enters the gutlumen.
Funbound.plasma	Fraction of plasma that is not bound.
Qtotal.liverc	Flow rate of blood exiting the liver, L/h/kg BW^3/4.
Qgfrc	Glomerular Filtration Rate, L/h/kg BW^3/4, volume of fluid filtered from kidney and excreted.
BW	Body Weight, kg
MW	Molecular Weight, g/mol
million.cells.per.gliver	Millions cells per gram of liver tissue.
Vliverc	Volume of the liver per kg body weight, L/kg BW.
liver.density	Liver tissue density, kg/L.
Fhep.assay.correction	The fraction of chemical unbound in hepatocyte assay using the method of Kilford et al. (2008)
hepatic.bioavailability	Fraction of dose remaining after first pass clearance, calculated from the corrected well-stirred model.

Author(s)

John Wambaugh and Greg Honda

References

\insertRef

pearce2017httkhttk

\insertRef

kilford2008hepatocellularhttk

See Also

calc_analytic_css_3compss

apply_clint_adjustment

tissue.data

physiology.data

Examples

 parameters <- parameterize_steadystate(chem.name='Bisphenol-A',species='Rat')
 parameters <- parameterize_steadystate(chem.cas='80-05-7')

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