solve_3comp {httk}

Solve_3comp

Description

This function solves for the amounts or concentrations of a chemical in different tissues as functions of time based on the dose and dosing frequency. It uses a three compartment model with partition coefficients.

Usage

solve_3comp(
  chem.name = NULL,
  chem.cas = NULL,
  dtxsid = NULL,
  times = NULL,
  parameters = NULL,
  days = 10,
  tsteps = 4,
  daily.dose = NULL,
  dose = NULL,
  doses.per.day = NULL,
  initial.values = NULL,
  plots = FALSE,
  suppress.messages = FALSE,
  species = "Human",
  iv.dose = FALSE,
  input.units = "mg/kg",
  output.units = NULL,
  method = "lsoda",
  rtol = 1e-08,
  atol = 1e-12,
  default.to.human = FALSE,
  recalc.blood2plasma = FALSE,
  recalc.clearance = FALSE,
  clint.pvalue.threshold = 0.05,
  dosing.matrix = NULL,
  adjusted.Funbound.plasma = TRUE,
  regression = TRUE,
  restrictive.clearance = TRUE,
  minimum.Funbound.plasma = 1e-04,
  Caco2.options = list(),
  monitor.vars = NULL,
  ...
)

Arguments

chem.name

Either the chemical name, CAS number, or the parameters must be specified.

chem.cas

Either the chemical name, CAS number, or the parameters must be specified.

dtxsid

EPA's 'DSSTox Structure ID (https://comptox.epa.gov/dashboard) the chemical must be identified by either CAS, name, or DTXSIDs

times

Optional time sequence for specified number of days. The dosing sequence begins at the beginning of times.

parameters

Chemical parameters from parameterize_3comp function, overrides chem.name and chem.cas.

days

Length of the simulation.

tsteps

The number time steps per hour.

daily.dose

Total daily dose, mg/kg BW.

dose

Amount of a single dose, mg/kg BW.

doses.per.day

Number of doses per day.

initial.values

Vector containing the initial concentrations or amounts of the chemical in specified tissues with units corresponding to output.units. Defaults are zero.

plots

Plots all outputs if true.

suppress.messages

Whether or not the output message is suppressed.

species

Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human").

iv.dose

Simulates a single i.v. dose if true.

input.units

Input units of interest assigned to dosing, defaults to mg/kg BW

output.units

A named vector of output units expected for the model results. Default, NULL, returns model results in units specified in the 'modelinfo' file. See table below for details.

method

Method used by integrator (deSolve).

rtol

Argument passed to integrator (deSolve).

atol

Argument passed to integrator (deSolve).

default.to.human

Substitutes missing animal values with human values if true (hepatic intrinsic clearance or fraction of unbound plasma).

recalc.blood2plasma

Recalculates the ratio of the amount of chemical in the blood to plasma using the input parameters, calculated with hematocrit, Funbound.plasma, and Krbc2pu.

recalc.clearance

Recalculates the the hepatic clearance (Clmetabolism) with new million.cells.per.gliver parameter.

clint.pvalue.threshold

Hepatic clearances with clearance assays having p-values greater than the threshold are set to zero.

dosing.matrix

Vector of dosing times or a matrix consisting of two columns or rows named "dose" and "time" containing the time and amount, in mg/kg BW, of each dose.

adjusted.Funbound.plasma

Uses adjusted Funbound.plasma when set to TRUE along with partition coefficients calculated with this value.

regression

Whether or not to use the regressions in calculating partition coefficients.

restrictive.clearance

Protein binding not taken into account (set to 1) in liver clearance if FALSE.

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.

monitor.vars

Which variables are returned as a function of time. Defaults value of NULL provides "Cliver", "Csyscomp", "Atubules", "Ametabolized", "AUC"

...

Additional arguments passed to the integrator.

Details

Note that the timescales for the model parameters have units of hours while the model output is in days.

Default of NULL for doses.per.day solves for a single dose.

The compartments used in this model are the gutlumen, gut, liver, and rest-of-body, with the plasma equivalent to the liver plasma.

Model Figure

When species is specified as rabbit, dog, or mouse, the function uses the appropriate physiological data(volumes and flows) but substitues human fraction unbound, partition coefficients, and intrinsic hepatic clearance.

Value

A matrix of class deSolve with a column for time(in days) and each compartment, the plasma concentration, area under the curve, and a row for each time point.

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.

See Also

solve_model

parameterize_3comp

calc_analytic_css_3comp

Examples

solve_3comp(chem.name='Bisphenol-A', 
            doses.per.day=2, 
            daily.dose=.5,
            days=1,
            tsteps=2)

# By storing the model parameters in a vector first, you can potentially
# edit them before using the model:
params <-parameterize_3comp(chem.cas="80-05-7")
solve_3comp(parameters=params, days=1)

head(solve_3comp(chem.name="Terbufos", daily.dose=NULL, dose=1, days=1))
head(solve_3comp(chem.name="Terbufos", daily.dose=NULL, dose=1, 
                 days=1, iv.dose=TRUE))

# A dose matrix specifies times and magnitudes of doses:
dm <- matrix(c(0,1,2,5,5,5),nrow=3)
colnames(dm) <- c("time","dose")
solve_3comp(chem.name="Methenamine", dosing.matrix=dm,
            dose=NULL, daily.dose=NULL,
            days=2.5)

solve_3comp(chem.name="Besonprodil",
            daily.dose=1, dose=NULL,
            days=2.5, doses.per.day=4)