R/Parameterize_SteadyState.R

In wwiecek/httkgui: High-Throughput Toxicokinetics: Analtica Laser prototype

# This function retrieves the paramters needed to run the constant infusion dose model for determining steady-state concentration.

parameterize_steadystate <- function(chem.cas=NULL,chem.name=NULL,species="Human",
                                     clint.pvalue.threshold=0.05,default.to.human=F,human.clint.fub=F)

{
  physiology.data <- physiology.data
  tissue.data <- tissue.data
# Look up the chemical name/CAS, depending on what was provide:
  out <- get_chem_id(chem.cas=chem.cas,chem.name=chem.name)
  chem.cas <- out$chem.cas
  chem.name <- out$chem.name

  #Capitilie the first letter of spcies only:
  species <- tolower(species)
  substring(species,1,1) <- toupper(substring(species,1,1))

  if (!(species %in% colnames(physiology.data)))
  {
    if (toupper(species) %in% toupper(colnames(physiology.data)))
    {
      phys.species <- colnames(physiology.data)[toupper(colnames(physiology.data))==toupper(species)]
    } else stop(paste("Physiological PK data for",species,"not found."))
  } else phys.species <- species
  this.phys.data <- physiology.data[,phys.species]
  names(this.phys.data) <- physiology.data[,1]
  
  QGFRc <- this.phys.data[["GFR"]] #mL/min/kgBW
  BW <- this.phys.data[["Average BW"]]
    
  if (!(paste(species,"Vol (L/kg)") %in% colnames(tissue.data)))
  {
    if (toupper(paste(species,"Vol (L/kg)")) %in% toupper(colnames(tissue.data)))
    {
      tissue.vols <- tissue.data[,toupper(colnames(tissue.data))==toupper(paste(species,"Vol (L/kg)"))]
      tissue.flows <- tissue.data[,toupper(colnames(tissue.data))==toupper(paste(species,"Flow (mL/min/kg^(3/4))"))]
    } else stop(paste("Tissue data for",species,"not found."))
  } else {
    tissue.vols <- tissue.data[,paste(species,"Vol (L/kg)")]
    tissue.flows <- tissue.data[,paste(species,"Flow (mL/min/kg^(3/4))")]
  }
  names(tissue.vols) <- tissue.data[,1]
  names(tissue.flows) <- tissue.data[,1]

  Qtotal.liverc <- tissue.flows[["liver"]]  #mL/min/kgBW
  Vliverc <- tissue.vols[["liver"]] # L/kg BW
  Clint <- try(get_invitroPK_param("Clint",species,chem.CAS=chem.cas),silent=T)
  if (class(Clint) == "try-error" & default.to.human || human.clint.fub) 
  {
    Clint <- try(get_invitroPK_param("Clint","Human",chem.CAS=chem.cas),silent=T)
    warning(paste(species,"coerced to Human for metabolic clerance data."))
  }
  if (class(Clint) == "try-error") stop("Missing metabolic clearance data for given species. Set default.to.human to true to substitute human value.")
    # Check that the trend in the CLint assay was significant:
  Clint.pValue <- get_invitroPK_param("Clint.pValue",species,chem.CAS=chem.cas)
  if (!is.na(Clint.pValue) & Clint.pValue > clint.pvalue.threshold) Clint <- 0
  
  # unitless fraction of chemical unbound with plasma
  fub <- try(get_invitroPK_param("Funbound.plasma",species,chem.CAS=chem.cas),silent=T)
  if (class(fub) == "try-error" & default.to.human || human.clint.fub) 
  {
    fub <- try(get_invitroPK_param("Funbound.plasma","Human",chem.CAS=chem.cas),silent=T)
    warning(paste(species,"coerced to Human for protein binding data."))
  }
  if (class(fub) == "try-error") stop("Missing protein binding data for given species. Set default.to.human to true to substitute human value.")
  if (fub == 0)
  {
    fub <- 0.005
    warning("Fraction unbound = 0, changed to 0.005.")
  }
  
  Fgutabs <- try(get_invitroPK_param("Fgutabs",species,chem.CAS=chem.cas),silent=T)
  if (class(Fgutabs) == "try-error") Fgutabs <- 1
 

  Params <- list()
  Params[["Clint"]] <- Clint # uL/min/10^6
  Params[["Funbound.plasma"]] <- fub # unitless fraction
  Params[["Qtotal.liverc"]] <- Qtotal.liverc/1000*60     #        L/h/kgBW
  Params[["Qgfrc"]] <- QGFRc/1000*60 #        L/h/kgBW     
  Params[["BW"]] <- BW # kg
  Params[["MW"]] <- get_physchem_param("MW",chem.CAS=chem.cas) # molecular weight g/mol
  
  pKa_Donor <- suppressWarnings(get_physchem_param("pKa_Donor",chem.CAS=chem.cas)) # acid dissociation constants
  pKa_Accept <- suppressWarnings(get_physchem_param("pKa_Accept",chem.CAS=chem.cas)) # basic association cosntants
  Pow <- 10^get_physchem_param("logP",chem.CAS=chem.cas) # Octanol:water partition coeffiecient

# Correct for unbound fraction of chemical in the hepatocyte intrinsic clearance assay (Kilford et al., 2008)
  Params[["Fhep.assay.correction"]] <- calc_fu_hep(Pow,pKa_Donor=pKa_Donor,pKa_Accept=pKa_Accept) # fraction 

  Params[["million.cells.per.gliver"]] <- 110 # 10^6 cells/g-liver
  Params[["Vliverc"]] <- Vliverc # L/kg BW
  Params[["liver.density"]] <- 1.05 # g/mL
  Params[['Fgutabs']] <- Fgutabs

  return(Params)
}