R/calc_analytic_css_3comp.R

In httk: High-Throughput Toxicokinetics

#'Calculate the analytic steady state concentration for model 3comp
#'
#'This function calculates the analytic steady state plasma or venous blood 
#'concentrations as a result of infusion dosing.
#'
#'@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 parameters Chemical parameters from parameterize_pbtk (for model = 
#' 'pbtk'), parameterize_3comp (for model = '3compartment), 
#' parameterize_1comp(for model = '1compartment') or parameterize_steadystate 
#' (for model = '3compartmentss'), overrides chem.name and chem.cas.
#'@param hourly.dose Hourly dose rate mg/kg BW/h.
#'@param concentration Desired concentration type, 'blood' or default 'plasma'.
#'@param suppress.messages Whether or not the output message is suppressed.
#'@param recalc.blood2plasma Recalculates the ratio of the amount of chemical 
#' in the blood to plasma using the input parameters. Use this if you have 
#' 'altered hematocrit, Funbound.plasma, or Krbc2pu.
#'@param tissue Desired tissue conentration (defaults to whole body 
#' concentration.)
#'@param restrictive.clearance If TRUE (default), then only the fraction of
#' chemical not bound to protein is available for metabolism in the liver. If 
#' FALSE, then all chemical in the liver is metabolized (faster metabolism due
#' to rapid off-binding). 
#'@param bioactive.free.invivo If FALSE (default), then the total concentration is treated
#' as bioactive in vivo. If TRUE, the the unbound (free) plasma concentration is treated as 
#' bioactive in vivo. Only works with \code{tissue = NULL} in current implementation.
#' 
#' @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 ... Additional parameters passed to parameterize function if 
#' parameters is NULL.
#'  
#'@return Steady state plasma concentration in mg/L units
#'
#' @seealso \code{\link{calc_analytic_css}}
#'
#' @seealso \code{\link{parameterize_3comp}}
#'
#'@author Robert Pearce and John Wambaugh
#'
#' @references 
#' \insertRef{pearce2017httk}{httk} 
#'
#'@keywords 3compartment
calc_analytic_css_3comp <- function(chem.name=NULL,
                                   chem.cas = NULL,
                                   dtxsid=NULL,
                                   parameters=NULL,
                                   hourly.dose=1/24,
                                   concentration='plasma',
                                   suppress.messages=FALSE,
                                   recalc.blood2plasma=FALSE,
                                   tissue=NULL,
                                   restrictive.clearance=TRUE,
                                   bioactive.free.invivo = FALSE,
                                   Caco2.options = list(),
                                   ...)
{
  #R CMD CHECK throws notes about "no visible binding for global variable", for
  #each time a data.table column name is used without quotes. To appease R CMD
  #CHECK, a variable has to be created for each of these column names and set to
  #NULL. Note that within the data.table, these variables will not be NULL! Yes,
  #this is pointless and annoying.
  dose <- NULL
  #End R CMD CHECK appeasement.
  
  param.names.3comp <- model.list[["3compartment"]]$param.names
  param.names.schmitt <- model.list[["schmitt"]]$param.names
    
# We need to describe the chemical to be simulated one way or another:
  if (is.null(chem.cas) & 
      is.null(chem.name) & 
      is.null(dtxsid) &
      is.null(parameters)) 
    stop('parameters, chem.name, chem.cas, or dtxsid must be specified.')

# Look up the chemical name/CAS, depending on what was provide:
  if (is.null(parameters))
  {
    out <- get_chem_id(
            chem.cas=chem.cas,
            chem.name=chem.name,
            dtxsid=dtxsid)
    chem.cas <- out$chem.cas
    chem.name <- out$chem.name                                
    dtxsid <- out$dtxsid  

    parameters <- parameterize_3comp(chem.cas=chem.cas,
                                    chem.name=chem.name,
                                    suppress.messages=suppress.messages,
                                    Caco2.options = Caco2.options,
                                    ...)
    if (recalc.blood2plasma) 
    {
      warning("Argument recalc.blood2plasma=TRUE ignored because parameters is NULL.")
    }
  } else {
    if (!all(param.names.3comp %in% names(parameters)))
    {
      stop(paste("Missing parameters:",
           paste(param.names.3comp[which(!param.names.3comp %in% names(parameters))],
             collapse=', '),
           ".  Use parameters from parameterize_3comp."))
    }
    param.names.pbtk <- model.list[["pbtk"]]$param.names 
    if (any(param.names.pbtk[which(!param.names.pbtk %in% param.names.3comp)] 
      %in% names(parameters)))
    {
      stop("Parameters are from parameterize_pbtk. Use parameters from parameterize_3comp instead.")
    }
    if (recalc.blood2plasma) parameters[['Rblood2plasma']] <- 1 - 
      parameters[['hematocrit']] + 
      parameters[['hematocrit']] * parameters[['Krbc2pu']] * parameters[['Funbound.plasma']]
  }
  param.names.schmitt <- model.list[["schmitt"]]$param.names


  hourly.dose <- hourly.dose * parameters$Fabsgut
  fup <- parameters$Funbound.plasma
  Rblood2plasma <- parameters$Rblood2plasma
  Clmetabolism <- parameters$Clmetabolismc
  if (!restrictive.clearance) Clmetabolism <- Clmetabolism / fup
  
  # Steady-state blood concentration:
  Css_blood <- hourly.dose * parameters[['BW']]^0.25  / 
    (Clmetabolism * parameters[['BW']]^0.25 + 
    parameters$Qgfrc * (parameters$Qliverf + 
    parameters$Qgutf) * parameters$Qcardiacc / 
    ((parameters$Qliverf + parameters$Qgutf) * parameters$Qcardiacc + 
    fup * parameters$Qgfrc / parameters$Rblood2plasma)) / fup
  Css <- Css_blood/ Rblood2plasma
  
# Check to see if a specific tissue was asked for:
  if (!is.null(tissue))
  {
# Need to convert to Schmitt parameters:
    #The parameters used in predict_partitioning_schmitt may be a compound
    #data.table/data.frame or list object, however, depending on the source 
    #of the parameters. In calc_mc_css, for example, parameters is received 
    #as a "data.table" object. Screen for processing appropriately.
    if (any(class(parameters) == "data.table")){
      pcs <- predict_partitioning_schmitt(parameters =
          parameters[, param.names.schmitt[param.names.schmitt %in% 
          names(parameters)], with = F])
    }else if (is(parameters,"list")) {
      pcs <- predict_partitioning_schmitt(parameters =
          parameters[param.names.schmitt[param.names.schmitt %in% 
          names(parameters)]])
    }else stop('httk is only configured to process parameters as objects of 
               class list or class compound data.table/data.frame.')
    
    if (!paste0('K',tolower(tissue)) %in% 
      substr(names(pcs),1,nchar(names(pcs))-3))
    {
      stop(paste("Tissue",tissue,"is not available."))
    }
# Tissues with sources (gut) or sinks (liver,kidney) need to be calculated
# taking the change of mass into account:
    if (tissue == 'gut')
    {
      Qgut <- parameters$Qgutf * parameters$Qcardiacc / parameters$BW^0.25
      Css <- parameters[['Kgut2pu']] * fup * 
        (Css + dose / (Qgut * Rblood2plasma))
    } else if (tissue == 'liver') {
      Qliver <- (parameters$Qgutf + parameters$Qliverf) * parameters$Qcardiacc / 
        parameters$BW^0.25
      Clmetabolism <- parameters$Clmetabolismc
      if (!restrictive.clearance) Clmetabolism <- Clmetabolism / fup
      Css <- parameters[['Kliver2pu']] * fup * (hourly.dose + 
        Qliver * Css * Rblood2plasma) / 
        (Clmetabolism * fup + Qliver * Rblood2plasma)
    } else {
      Css <- Css * pcs[[names(pcs)[substr(names(pcs),2,nchar(names(pcs))-3)==tissue]]] * fup   
    }
  }
  

  if(tolower(concentration) != 'tissue'){
    if (tolower(concentration)=='blood')
    {
      Css <- Css * parameters[['Rblood2plasma']]
      
    }else if(bioactive.free.invivo == TRUE & tolower(concentration) == 'plasma'){
      
      Css <- Css * parameters[['Funbound.plasma']]
      
    } else if (tolower(concentration)!='plasma') stop("Only blood and plasma concentrations are calculated.")
  }
  
  return(Css)
}