calc_analytic_css_pbtk {httk}

Calculate the analytic steady state plasma concentration for model pbtk.

Description

This function calculates the analytic steady state concentration (mg/L) as a result of oral infusion dosing. Concentrations are returned for plasma by default, but various tissues or blood concentrations can also be given as specified.

Usage

calc_analytic_css_pbtk(
  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(),
  ...
)

Arguments

chem.name

Either the chemical name, CAS number, or the parameters must be specified.

chem.cas

Either the chemical name, CAS number, or the parameters must be specified.

dtxsid

EPA's 'DSSTox Structure ID (https://comptox.epa.gov/dashboard) the chemical must be identified by either CAS, name, or DTXSIDs

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.

hourly.dose

Hourly dose rate mg/kg BW/h.

concentration

Desired concentration type, 'blood', 'tissue', or default 'plasma'.

suppress.messages

Whether or not the output message is suppressed.

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.

tissue

Desired tissue conentration (defaults to whole body concentration.)

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).

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 tissue = NULL in current implementation.

Caco2.options

A list of options to use when working with Caco2 apical to basolateral data 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 = Fabs. Caco2.Fgut = TRUE uses Caco2.Pab to calculate fgut.oral, otherwise fgut.oral = 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 get_fabsgut for further details.

...

Additional parameters passed to parameterize function if parameters is NULL.

Details

The PBTK model (Pearce et al., 2017) predicts the amount of chemical in various tissues of the body. A system of oridinary differential equations describes how the amounts in each tissue change as a function of time. The analytic steady-state equation was found by algebraically solving for the tissue concentrations that result in each equation being zero – thus determining the concentration at which there is no change over time as the result of a fixed infusion dose rate.

The analytical solution is:

C^{ss}_{ven} = \frac{dose rate * \frac{Q_{liver} + Q_{gut}}{\frac{f_{up}}{R_{b:p}}*Cl_{metabolism} + (Q_{liver}+Q_{gut})}}{Q_{cardiac} - \frac{(Q_{liver} + Q_{gut})^2}{\frac{f_{up}}{R_{b:p}}*Cl_{metabolism} + (Q_{liver}+Q_{gut})} - \frac{(Q_{kidney})^2}{\frac{f_{up}}{R_{b:p}}*Q_{GFR}+Q_{kideny}}-Q_{rest}}

C^{ss}_{plasma} = \frac{C^{ss}_{ven}}{R_{b:p}}

C^{ss}_{tissue} = \frac{K_{tissue:fuplasma}*f_{up}}{R_{b:p}}*C^{ss}_{ven}

where Q_cardiac is the cardiace output, Q_gfr is the glomerular filtration rate in the kidney, other Q's indicate blood flows to various tissues, Cl_metabolism is the chemical-specific whole liver metabolism clearance, f_up is the chemical-specific fraction unbound n plasma, R_b2p is the chemical specific ratio of concentrations in blood:plasma, K_tissue2fuplasma is the chemical- and tissue-specufic equilibrium partition coefficient and dose rate has units of mg/kg/day.

Value

Steady state plasma concentration in mg/L units

Author(s)

Robert Pearce and John Wambaugh

References

Pearce RG, Setzer RW, Strope CL, Wambaugh JF, Sipes NS (2017). “Httk: R package for high-throughput toxicokinetics.” Journal of Statistical Software, 79(4), 1.

See Also

calc_analytic_css

parameterize_pbtk