R: Parameters for a generic physiologically-based toxicokinetic...

parameterize_pbtk {httk}

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,
  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").
`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))
`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.

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).

The default PBTK model includes an explicit first pass of the chemical through the liver before it becomes available to systemic blood. We model systemic oral bioavailability as F_bio=F_abs*F_gut*F_hep. Only 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 where F_hep is estimated from in vitro TK data using calc_hep_bioavailability. 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

`BW`	Body Weight, kg.
`Clmetabolismc`	Hepatic Clearance, L/h/kg BW.
`Fabsgut`	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 RG, Setzer RW, Strope CL, Wambaugh JF, Sipes NS (2017). “Httk: R package for high-throughput toxicokinetics.” Journal of Statistical Software, 79(4), 1.

Schmitt W (2008). “General approach for the calculation of tissue to plasma partition coefficients.” Toxicology in vitro, 22(2), 457–467.

Pearce RG, Setzer RW, Davis JL, Wambaugh JF (2017). “Evaluation and calibration of high-throughput predictions of chemical distribution to tissues.” Journal of pharmacokinetics and pharmacodynamics, 44, 549–565.

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.

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

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)

[Package httk version 2.3.1 Index]