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#' Solve_3comp
#'
#' 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.
#'
#' 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
#' \if{html}{\figure{3comp.jpg}{options: width="60\%" alt="Figure: Three
#' Compartment Model Schematic"}}
#' \if{latex}{\figure{3comp.pdf}{options: width=12cm alt="Figure: Three Compartment
#' Model Schematic"}}
#'
#' 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.
#'
#'
#'
#' @param chem.name Either the chemical name, CAS number, or the parameters
#' must be specified.
#' @param chem.cas Either the chemical name, CAS number, or the parameters must
#' be specified.
#' @param dtxsid EPA's 'DSSTox Structure ID (\url{https://comptox.epa.gov/dashboard})
#' the chemical must be identified by either CAS, name, or DTXSIDs
#' @param times Optional time sequence for specified number of days. The
#' dosing sequence begins at the beginning of times.
#' @param parameters Chemical parameters from parameterize_3comp function,
#' overrides chem.name and chem.cas.
#' @param days Length of the simulation.
#' @param tsteps The number time steps per hour.
#' @param daily.dose Total daily dose, mg/kg BW.
#' @param dose Amount of a single dose, mg/kg BW.
#' @param doses.per.day Number of doses per day.
#' @param initial.values Vector containing the initial concentrations or
#' amounts of the chemical in specified tissues with units corresponding to
#' output.units. Defaults are zero.
#' @param plots Plots all outputs if true.
#' @param suppress.messages Whether or not the output message is suppressed.
#' @param species Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or
#' default "Human").
#' @param iv.dose Simulates a single i.v. dose if true.
#' @param input.units Input units of interest assigned to dosing,
#' defaults to mg/kg BW
#' @param 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.
#' @param method Method used by integrator (deSolve).
#' @param rtol Argument passed to integrator (deSolve).
#' @param atol Argument passed to integrator (deSolve).
#' @param default.to.human Substitutes missing animal values with human values
#' if true (hepatic intrinsic clearance or fraction of unbound plasma).
#' @param 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.
#' @param clint.pvalue.threshold Hepatic clearances with clearance assays
#' having p-values greater than the threshold are set to zero.
#' @param recalc.clearance Recalculates the the hepatic clearance
#' (Clmetabolism) with new million.cells.per.gliver parameter.
#' @param 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.
#' @param adjusted.Funbound.plasma Uses adjusted Funbound.plasma when set to
#' TRUE along with partition coefficients calculated with this value.
#' @param regression Whether or not to use the regressions in calculating
#' partition coefficients.
#' @param restrictive.clearance Protein binding not taken into account (set to
#' 1) in liver clearance if FALSE.
#' @param 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).
#' @param Caco2.options A list of options to use when working with Caco2 apical to
#' basolateral data \code{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 = \code{Fabs}. Caco2.Fgut = TRUE uses Caco2.Pab to calculate
#' fgut.oral, otherwise fgut.oral = \code{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 \code{\link{get_fabsgut}} for further details.
#'
#' @param monitor.vars Which variables are returned as a function of time.
#' Defaults value of NULL provides "Cliver", "Csyscomp", "Atubules",
#' "Ametabolized", "AUC"
#' @param ... Additional arguments passed to the integrator.
#'
#' @return 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 John Wambaugh and Robert Pearce
#'
#' @references
#' \insertRef{pearce2017httk}{httk}
#'
#' @keywords Solve 3compartment
#'
#' @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)
#'
#' @seealso \code{\link{solve_model}}
#'
#' @seealso \code{\link{parameterize_3comp}}
#'
#' @seealso \code{\link{calc_analytic_css_3comp}}
#'
#' @export solve_3comp
solve_3comp <- function(chem.name = NULL,
chem.cas = NULL,
dtxsid = NULL,
times=NULL,
parameters=NULL,
days=10,
tsteps = 4, # tsteps is number of steps per hour
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='uM',
output.units=NULL,
method="lsoda",rtol=1e-8,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=0.0001,
Caco2.options = list(),
monitor.vars=NULL,
...)
{
out <- solve_model(
chem.name = chem.name,
chem.cas = chem.cas,
dtxsid = dtxsid,
times=times,
parameters=parameters,
model="3compartment",
route=ifelse(iv.dose,"iv","oral"),
dosing=list(
initial.dose=dose,
dosing.matrix=dosing.matrix,
daily.dose=daily.dose,
doses.per.day=doses.per.day
),
days=days,
tsteps = tsteps, # tsteps is number of steps per hour
initial.values=initial.values,
plots=plots,
monitor.vars=monitor.vars,
suppress.messages=suppress.messages,
species=species,
input.units=input.units,
output.units=output.units,
method=method,rtol=rtol,atol=atol,
recalc.blood2plasma=recalc.blood2plasma,
recalc.clearance=recalc.clearance,
adjusted.Funbound.plasma=adjusted.Funbound.plasma,
minimum.Funbound.plasma=minimum.Funbound.plasma,
parameterize.arg.list=list(
default.to.human=default.to.human,
clint.pvalue.threshold=clint.pvalue.threshold,
restrictive.clearance = restrictive.clearance,
regression=regression,
Caco2.options=Caco2.options),
...)
out <- cbind(out,out[,"Csyscomp"])
colnames(out)[length(colnames(out))]<-"Cplasma"
return(out)
}
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