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

In httk: High-Throughput Toxicokinetics

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 \insertCiteyang2007prediction;textualhttk. These functions calculate the fraction absorbed (calc_fabs.oral – \insertCitedarwich2010interplay;textualhttk and \insertCiteyu1999compartmental;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 (\insertCitelennernas1997human;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
)

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

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).

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).

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(s)

Gregory Honda and John Wambaugh

References

\insertRef

darwich2010interplayhttk \insertRefyang2007predictionhttk \insertRefHondaUnpublishedCaco2httk \insertRefyu1999compartmentalhttk \insertReflennernas1997humanhttk

httk documentation built on Sept. 11, 2024, 9:32 p.m.