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
)

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).

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.
Fgutabs	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

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

Schmitt, Walter. "General approach for the calculation of tissue to plasma partition coefficients." Toxicology in vitro 22.2 (2008): 457-467.

Pearce, Robert G., et al. "Evaluation and calibration of high-throughput predictions of chemical distribution to tissues." Journal of pharmacokinetics and pharmacodynamics 44.6 (2017): 549-565.

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

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)

httk documentation built on March 7, 2023, 7:26 p.m.