calc_fbio.oral {httk}

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 Yang et al. (2007). These functions calculate the fraction absorbed (calc_fabs.oral – S Darwich et al. (2010)), 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 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}).

Usage

calc_fbio.oral(
  parameters = NULL,
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  species = "Human",
  default.to.human = FALSE,
  suppress.messages = 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_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'.)

Caco2.Pab.default

(Numeric) Caco2 apical to basolateral data. (Defaults to 1.6.) (Not applicable for 'calc_fbio.oral'.)

Details

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.

Functions

• calc_fabs.oral(): Calculate the fraction absorbed in the gut (Darwich et al., 2010)

• calc_fgut.oral(): Calculate the fraction of chemical surviving first pass metabolism in the gut

Author(s)

Gregory Honda

References

S Darwich A, Neuhoff S, Jamei M, Rostami-Hodjegan A (2010). “Interplay of metabolism and transport in determining oral drug absorption and gut wall metabolism: a simulation assessment using the 'Advanced Dissolution, Absorption, Metabolism (ADAM)' model.” Current drug metabolism, 11(9), 716–729. Yang J, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A (2007). “Prediction of intestinal first-pass drug metabolism.” Current drug metabolism, 8(7), 676–684. Honda G, Kenyon EM, Davidson-Fritz SE, Dinallo R, El-Masri H, Korel-Bexell E, Li L, Paul-Friedman K, Pearce R, Sayre R, Strock C, Thomas R, Wetmore BA, Wambaugh JF (2023). “Impact of Gut Permeability on Estimation of Oral Bioavailability for Chemicals in Commerce and the Environment.” Unpublished.