calc_fbio.oral: Functions for calculating the bioavaialble fractions from oral doses

Description

These functions calculate the fraction of chemical absorbed from the gut based upon in vitro measured Caco-2 membrane permeability data. Caco-2 permeabilities (\(10^{-6}\) cm/s) are related to effective permeability based on yang2007prediction;textualhttk. These functions calculate the fraction absorbed (calc_fabs.oral -- darwich2010interplay;textualhttk and yu1999compartmental;textualhttk), the fraction surviving first pass gut metabolism (calc_fgut.oral), and the overall systemic oral bioavailability (calc_fbio.oral). Note that the first pass hepatic clearance is calculated within the parameterization and other functions. using calc_hep_bioavailability Absorption rate is calculated according to Fick's law (lennernas1997human;textualhttk) assuming low blood concentrations.

Usage

calc_fbio.oral(
  parameters = NULL,
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  species = "Human",
  default.to.human = FALSE,
  suppress.messages = FALSE,
  restrictive.clearance = FALSE
)
calc_fabs.oral(
  parameters = NULL,
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  species = "Human",
  suppress.messages = FALSE,
  Caco2.Pab.default = 1.6
)
calc_peff(
  parameters = NULL,
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  species = "Human",
  default.to.human = FALSE,
  suppress.messages = FALSE,
  Caco2.Pab = NULL
)
calc_kgutabs(
  parameters = NULL,
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  species = "Human",
  default.to.human = FALSE,
  suppress.messages = FALSE
)
calc_fgut.oral(
  parameters = NULL,
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  species = "Human",
  default.to.human = FALSE,
  suppress.messages = FALSE,
  Caco2.Pab.default = 1.6
)

Value

fbio.oral: Oral bioavailability, the fraction of oral dose reaching systemic distribution in the body.
fabs.oral: Fraction of dose absorbed, i.e. the fraction of the dose that enters the gutlumen.
fgut.oral: Fraction of chemical surviving first pass metabolism in the gut.
fhep.oral: Fraction of chemical surviving first pass hepatic clearance.
kgutabs: Rate of absorption from gut (1/h).

Arguments

parameters: (List) A list of the parameters (Caco2.Pab, Funbound.Plasma, Rblood2plasma, Clint, BW, Qsmallintestine, Fabs, Fgut) used in the calculation, either supplied by user or calculated in parameterize_steadystate.
chem.cas: (Character) Chemical CAS number. (Defaults to `NULL`.) (Note: Either the chemical name, CAS number, or EPA's DSSTox Structure ID must be specified).
chem.name: (Character) Chemical name. (Defaults to `NULL`.) (Note: Either the chemical name, CAS number, or EPA's DSSTox Structure ID must be specified).
dtxsid: (Character) EPA's DSSTox Structure ID (https://comptox.epa.gov/dashboard). (Defaults to `NULL`.) (Note: Either the chemical name, CAS number, or EPA's DSSTox Structure ID must be specified).
species: (Character) Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human").
default.to.human: (Logical) Substitutes missing rat values with human values if TRUE. (Not applicable for `calc_fabs.oral`.) (Defaults to `FALSE`.)
suppress.messages: (Logical) Whether or not the output message is suppressed. (Defaults to `FALSE`.)
restrictive.clearance: Protein binding not taken into account (set to 1) in liver clearance if FALSE.
Caco2.Pab.default: (Numeric) Caco2 apical to basolateral data. (Defaults to 1.6.) (Not applicable for `calc_fbio.oral`.)
Caco2.Pab: (Numeric) Caco2 apical to basolaterial permeability used by calc_peff

Functions

calc_fabs.oral(): Calculate the fraction absorbed in the gut (Darwich et al., 2010)
calc_peff(): Calculate the effective gut permeability rate (10^-4 cm/s)
calc_kgutabs(): Calculate the gut absorption rate (1/h)
calc_fgut.oral(): Calculate the fraction of chemical surviving first pass metabolism in the gut

Author

Gregory Honda and John Wambaugh

Details

We assume that systemic oral bioavailability (\(F_{bio}\)) consists of three components: (1) the fraction of chemical absorbed from intestinal lumen into enterocytes (\(F_{abs}\)), (2) the fraction surviving intestinal metabolism (\(F_{gut}\)), and (3) the fraction surviving first-pass hepatic metabolism (\(F_{hep}\)). This function returns (\(F_{abs}*F_{gut}\)).

We model systemic oral bioavailability as \(F_{bio}=F_{abs}*F_{gut}*F_{hep}\). \(F_{hep}\) is estimated from in vitro TK data using calc_hep_bioavailability. 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 \(F_{hep}\). Otherwise, if Caco2 membrane permeability data or predictions are available \(F_{abs}\) is estimated using calc_fgut.oral. Intrinsic hepatic metabolism is used to very roughly estimate (\(F_{gut}\)) using calc_fgut.oral. If argument keepit100 is used then there is complete absorption from the gut (that is, \(F_{abs}=F_{gut}=1\)).

References

darwich2010interplayhttk yang2007predictionhttk HondaUnpublishedCaco2httk yu1999compartmentalhttk lennernas1997humanhttk