parameterize_steadystate {httk}

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,
  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).

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_fabsgut 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

Pearce RG, Setzer RW, Strope CL, Wambaugh JF, Sipes NS (2017). “Httk: R package for high-throughput toxicokinetics.” Journal of Statistical Software, 79(4), 1.

Kilford PJ, Gertz M, Houston JB, 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), 1194–1197.

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')