parameterize_pbtk: Parameters for a generic physiologically-based toxicokinetic...
In httk: High-Throughput Toxicokinetics

parameterize_pbtk

R Documentation

Parameters for a generic physiologically-based toxicokinetic model

Description

Generate a chemical- and species-specific set of PBPK model parameters. Parameters include tissue:plasma partition coefficients, organ volumes, and flows for the tissue lumping scheme specified by argument tissuelist. Tissure:(fraction unbound in) plasma partitition coefficients are predicted via Schmitt (2008)'s method as modified by Pearce et al. (2017) using predict_partitioning_schmitt. Organ volumes and flows are retrieved from table physiology.data. Tissues must be described in table tissue.data.

Usage

parameterize_pbtk(
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  species = "Human",
  default.to.human = FALSE,
  tissuelist = list(liver = c("liver"), kidney = c("kidney"), lung = c("lung"), gut =
    c("gut")),
  force.human.clint.fup = FALSE,
  clint.pvalue.threshold = 0.05,
  adjusted.Funbound.plasma = TRUE,
  adjusted.Clint = TRUE,
  regression = TRUE,
  suppress.messages = FALSE,
  restrictive.clearance = TRUE,
  minimum.Funbound.plasma = 1e-04,
  million.cells.per.gliver = 110,
  liver.density = 1.05,
  kgutabs = 2.18
)

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 animal values with human values if true (hepatic intrinsic clearance or fraction of unbound plasma).
`tissuelist`	Specifies compartment names and tissues groupings. Remaining tissues in tissue.data are lumped in the rest of the body. However, `solve_pbtk` only works with the default parameters.
`force.human.clint.fup`	Forces use of human values for hepatic intrinsic clearance and fraction of unbound plasma if true.
`clint.pvalue.threshold`	Hepatic clearance for chemicals where the in vitro clearance assay result has a p-values greater than the threshold are set to zero.
`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).
`regression`	Whether or not to use the regressions in calculating partition coefficients.
`suppress.messages`	Whether or not the output message is suppressed.
`restrictive.clearance`	In calculating hepatic.bioavailability, protein binding is not taken into account (set to 1) in liver clearance if FALSE.
`minimum.Funbound.plasma`	f_{up} is not allowed to drop below this value (default is 0.0001).
`million.cells.per.gliver`	Hepatocellularity (defaults to 110 10^6 cells/g-liver, from Carlile et al. (1997))
`liver.density`	Liver density (defaults to 1.05 g/mL from International Commission on Radiological Protection (1975))
`kgutabs`	Oral absorption rate from gut (defaults to 2.18 1/h from Wambaugh et al. (2018))

Details

By default, this function initializes the parameters needed in the functions solve_pbtk, calc_css, and others using the httk default generic PBTK model (for oral and intravenous dosing only).

Value

`BW`	Body Weight, kg.
`Clmetabolismc`	Hepatic Clearance, L/h/kg BW.
`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.
`Fhep.assay.correction`	The fraction of chemical unbound in hepatocyte assay using the method of Kilford et al. (2008)
`hematocrit`	Percent volume of red blood cells in the blood.
`Kgut2pu`	Ratio of concentration of chemical in gut tissue to unbound concentration in plasma.
`kgutabs`	Rate that chemical enters the gut from gutlumen, 1/h.
`Kkidney2pu`	Ratio of concentration of chemical in kidney tissue to unbound concentration in plasma.
`Kliver2pu`	Ratio of concentration of chemical in liver tissue to unbound concentration in plasma.
`Klung2pu`	Ratio of concentration of chemical in lung tissue to unbound concentration in plasma.
`Krbc2pu`	Ratio of concentration of chemical in red blood cells to unbound concentration in plasma.
`Krest2pu`	Ratio of concentration of chemical in rest of body tissue to unbound concentration in plasma.
`million.cells.per.gliver`	Millions cells per gram of liver tissue.
`MW`	Molecular Weight, g/mol.
`Qcardiacc`	Cardiac Output, L/h/kg BW^3/4.
`Qgfrc`	Glomerular Filtration Rate, L/h/kg BW^3/4, volume of fluid filtered from kidney and excreted.
`Qgutf`	Fraction of cardiac output flowing to the gut.
`Qkidneyf`	Fraction of cardiac output flowing to the kidneys.
`Qliverf`	Fraction of cardiac output flowing to the liver.
`Rblood2plasma`	The ratio of the concentration of the chemical in the blood to the concentration in the plasma from available_rblood2plasma.
`Vartc`	Volume of the arteries per kg body weight, L/kg BW.
`Vgutc`	Volume of the gut per kg body weight, L/kg BW.
`Vkidneyc`	Volume of the kidneys per kg body weight, L/kg BW.
`Vliverc`	Volume of the liver per kg body weight, L/kg BW.
`Vlungc`	Volume of the lungs per kg body weight, L/kg BW.
`Vrestc`	Volume of the rest of the body per kg body weight, L/kg BW.
`Vvenc`	Volume of the veins per kg body weight, L/kg BW.

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.

Carlile, David J., Katayoun Zomorodi, and J. Brian Houston. "Scaling factors to relate drug metabolic clearance in hepatic microsomes, isolated hepatocytes, and the intact liver: studies with induced livers involving diazepam." Drug metabolism and disposition 25.8 (1997): 903-911.

International Commission on Radiological Protection. Report of the task group on reference man. Vol. 23. Pergamon, Oxford. 1975.

Wambaugh, John F., et al. "Evaluating in vitro-in vivo extrapolation of toxicokinetics." Toxicological Sciences 163.1 (2018): 152-169.

Examples


 parameters <- parameterize_pbtk(chem.cas='80-05-7')

 parameters <- parameterize_pbtk(chem.name='Bisphenol-A',species='Rat')

 # Change the tissue lumping (note, these model parameters will not work with our current solver):
 compartments <- list(liver=c("liver"),fast=c("heart","brain","muscle","kidney"),
                      lung=c("lung"),gut=c("gut"),slow=c("bone"))
 parameterize_pbtk(chem.name="Bisphenol a",species="Rat",default.to.human=TRUE,
                   tissuelist=compartments)

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