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

View source: R/parameterize_steadystate.R

parameterize_steadystateR Documentation

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,
  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
)

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).

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).

Value

Clint

Hepatic Intrinsic Clearance, uL/min/10^6 cells.

Fgutabs

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.

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

References

Pearce, Robert G., et al. "Httk: R package for high-throughput toxicokinetics." Journal of statistical software 79.4 (2017): 1.

Kilford, P. J., Gertz, M., Houston, J. B. and Galetin, A. (2008). Hepatocellular binding of drugs: correction for unbound fraction in hepatocyte incubations using microsomal binding or drug lipophilicity data. Drug Metabolism and Disposition 36(7), 1194-7, 10.1124/dmd.108.020834.

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 March 7, 2023, 7:26 p.m.