parameterize_1comp: Parameters for a one compartment (empirical) toxicokinetic...

In httk: High-Throughput Toxicokinetics

Parameters for a one compartment (empirical) toxicokinetic model

Description

This function initializes the parameters needed in the function solve_1comp. Volume of distribution is estimated by using a modified Schmitt (2008) method to predict tissue particition coefficients (Pearce et al., 2017) and then lumping the compartments weighted by tissue volume:

Usage

parameterize_1comp(
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  species = "Human",
  default.to.human = FALSE,
  adjusted.Funbound.plasma = TRUE,
  adjusted.Clint = TRUE,
  regression = TRUE,
  restrictive.clearance = TRUE,
  well.stirred.correction = TRUE,
  suppress.messages = FALSE,
  clint.pvalue.threshold = 0.05,
  minimum.Funbound.plasma = 1e-04,
  Caco2.options = list()
)

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 rat values with human values if true.
adjusted.Funbound.plasma	Uses Pearce et al. (2017) lipid binding adjustment for Funbound.plasma (which impacts volume of distribution) 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 in volume of distribution calculation.
restrictive.clearance	In calculating elimination rate and hepatic bioavailability, protein binding is not taken into account (set to 1) in liver clearance if FALSE.
well.stirred.correction	Uses correction in calculation of hepatic clearance for well-stirred model if TRUE. This assumes clearance relative to amount unbound in whole blood instead of plasma, but converted to use with plasma concentration.
suppress.messages	Whether or not to suppress messages.
clint.pvalue.threshold	Hepatic clearance for chemicals where the in vitro clearance assay result has a p-value greater than the threshold are set to zero.
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.

Details

V_d,steady-state = Sum over all tissues (K_i * V_i) + V_plasma

where K_i is the tissue:unbound plasma concentration partition coefficient for tissue i.

Value

Vdist	Volume of distribution, units of L/kg BW.
Fabsgut	Fraction of the oral dose absorbed and surviving gut metabolism, i.e. the fraction of the dose that enters the gutlumen.
kelim	Elimination rate, units of 1/h.
hematocrit	Percent volume of red blood cells in the blood.
Fabsgut	Fraction of the oral dose absorbed, i.e. the fraction of the dose that enters the gutlumen.
Fhep.assay.correction	The fraction of chemical unbound in hepatocyte assay using the method of Kilford et al. (2008)
kelim	Elimination rate, units of 1/h.
hematocrit	Percent volume of red blood cells in the blood.
kgutabs	Rate chemical is absorbed, 1/h.
million.cells.per.gliver	Millions cells per gram of liver tissue.
MW	Molecular Weight, g/mol.
Rblood2plasma	The ratio of the concentration of the chemical in the blood to the concentration in the plasma. Not used in calculations but included for the conversion of plasma outputs.
hepatic.bioavailability	Fraction of dose remaining after first pass clearance, calculated from the corrected well-stirred model.
BW	Body Weight, kg.

Author(s)

John Wambaugh and Robert Pearce

References

\insertRef

pearce2017httkhttk

\insertRef

schmitt2008generalhttk

\insertRef

pearce2017evaluationhttk

\insertRef

kilford2008hepatocellularhttk

See Also

solve_1comp

calc_analytic_css_1comp

calc_vdist

parameterize_steadystate

apply_clint_adjustment

tissue.data

physiology.data

Examples

 parameters <- parameterize_1comp(chem.name='Bisphenol-A',species='Rat')
 parameters <- parameterize_1comp(chem.cas='80-05-7',
                                  restrictive.clearance=FALSE,
                                  species='rabbit',
                                  default.to.human=TRUE)
 out <- solve_1comp(parameters=parameters,days=1)

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