solve_pbtk | R Documentation |
This function solves for the amounts or concentrations in uM of a chemical
in different tissues as functions of time based on the dose and dosing
frequency.
In this PBTK formulation. C_{tissue}
is the concentration in tissue at
time t. Since the perfusion limited partition coefficients describe
instantaneous equilibrium between the tissue and the free fraction in
plasma, the whole plasma concentration is
C_{tissue,plasma} = \frac{1}{f_{up}*K_{tissue2fup}}*C_{tissue}
.
Note that we use a single,
constant value of f_{up}
across all tissues. Corespondingly the free
plasma
concentration is modeled as
C_{tissue,free plasma} = \frac{1}{K_{tissue2fup}}*C_tissue
.
The amount of blood flowing from tissue x is Q_{tissue}
(L/h) at a
concentration
C_{x,blood} = \frac{R_{b2p}}{f_{up}*K_{tissue2fup}}*C_{tissue}
, where
we use a
single R_{b2p}
value throughout the body.
Metabolic clearance is modelled as being from the total plasma
concentration here, though it is restricted to the free fraction in
calc_hep_clearance
by default. Renal clearance via
glomerulsr filtration is from the free plasma concentration.
The compartments used in this model are the gutlumen, gut, liver, kidneys,
veins, arteries, lungs, and the rest of the body.
The extra compartments include the amounts or concentrations metabolized by
the liver and excreted by the kidneys through the tubules.
AUC is the area under the curve of the plasma concentration.
solve_pbtk(
chem.name = NULL,
chem.cas = NULL,
dtxsid = NULL,
times = NULL,
parameters = NULL,
days = 10,
tsteps = 4,
daily.dose = NULL,
dose = NULL,
doses.per.day = NULL,
initial.values = NULL,
plots = FALSE,
suppress.messages = FALSE,
species = "Human",
iv.dose = FALSE,
input.units = "mg/kg",
output.units = NULL,
default.to.human = FALSE,
class.exclude = TRUE,
recalc.blood2plasma = FALSE,
recalc.clearance = FALSE,
dosing.matrix = NULL,
adjusted.Funbound.plasma = TRUE,
regression = TRUE,
restrictive.clearance = TRUE,
minimum.Funbound.plasma = 1e-04,
Caco2.options = list(),
monitor.vars = NULL,
...
)
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 |
times |
Optional time sequence for specified number of days. Dosing sequence begins at the beginning of times. |
parameters |
Chemical parameters from parameterize_pbtk function, overrides chem.name and chem.cas. |
days |
Length of the simulation. |
tsteps |
The number of time steps per hour. |
daily.dose |
Total daily dose, defaults to mg/kg BW. |
dose |
Amount of a single, initial oral dose in mg/kg BW. |
doses.per.day |
Number of doses per day. |
initial.values |
Vector containing the initial concentrations or amounts of the chemical in specified tissues with units corresponding to output.units. Defaults are zero. |
plots |
Plots all outputs if true. |
suppress.messages |
Whether or not the output message is suppressed. |
species |
Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human"). |
iv.dose |
Simulates a single i.v. dose if true. |
input.units |
Input units of interest assigned to dosing, defaults to mg/kg BW |
output.units |
A named vector of output units expected for the model results. Default, NULL, returns model results in units specified in the 'modelinfo' file. See table below for details. |
default.to.human |
Substitutes missing animal values with human values if true (hepatic intrinsic clearance or fraction of unbound plasma). |
class.exclude |
Exclude chemical classes identified as outside of domain of applicability by relevant modelinfo_[MODEL] file (default TRUE). |
recalc.blood2plasma |
Recalculates the ratio of the amount of chemical in the blood to plasma using the input parameters, calculated with hematocrit, Funbound.plasma, and Krbc2pu. |
recalc.clearance |
Recalculates the the hepatic clearance (Clmetabolism) with new million.cells.per.gliver parameter. |
dosing.matrix |
Vector of dosing times or a matrix consisting of two columns or rows named "dose" and "time" containing the time and amount, in mg/kg BW, of each dose. |
adjusted.Funbound.plasma |
Uses adjusted Funbound.plasma when set to TRUE along with partition coefficients calculated with this value. |
regression |
Whether or not to use the regressions in calculating partition coefficients. |
restrictive.clearance |
Protein binding not taken into account (set to 1) in liver clearance if FALSE. |
minimum.Funbound.plasma |
Monte Carlo draws less than this value are set equal to this value (default is 0.0001 – half the lowest measured Fup in our dataset). |
Caco2.options |
A list of options to use when working with Caco2 apical to
basolateral data |
monitor.vars |
Which variables are returned as a function of time. The default value of NULL provides "Cgut", "Cliver", "Cven", "Clung", "Cart", "Crest", "Ckidney", "Cplasma", "Atubules", "Ametabolized", and "AUC" |
... |
Additional arguments passed to the integrator (deSolve). |
Note that the model parameters have units of hours while the model output is in days.
Default NULL value for doses.per.day solves for a single dose.
Model Figure
When species is specified as rabbit, dog, or mouse, the function uses the appropriate physiological data(volumes and flows) but substitutes human fraction unbound, partition coefficients, and intrinsic hepatic clearance.
A matrix of class deSolve with a column for time(in days), each compartment, the area under the curve, and plasma concentration and a row for each time point.
John Wambaugh and Robert Pearce
pearce2017httkhttk
solve_model
parameterize_gas_pbtk
calc_analytic_css_pbtk
# Multiple doses per day:
head(solve_pbtk(
chem.name='Bisphenol-A',
daily.dose=.5,
days=2.5,
doses.per.day=2,
tsteps=2))
# Starting with an initial concentration:
out <- solve_pbtk(
chem.name='bisphenola',
dose=0,
days=2.5,
output.units="mg/L",
initial.values=c(Agut=200))
# Working with parameters (rather than having solve_pbtk retrieve them):
params <- parameterize_pbtk(chem.cas="80-05-7")
head(solve_pbtk(parameters=params, days=2.5))
# We can change the parameters given to us by parameterize_pbtk:
params <- parameterize_pbtk(dtxsid="DTXSID4020406", species = "rat")
params["Funbound.plasma"] <- 0.1
out <- solve_pbtk(parameters=params, days=2.5)
# A fifty day simulation:
out <- solve_pbtk(
chem.name = "Bisphenol A",
days = 50,
daily.dose=1,
doses.per.day = 3)
plot.data <- as.data.frame(out)
css <- calc_analytic_css(chem.name = "Bisphenol A")
library("ggplot2")
c.vs.t <- ggplot(plot.data, aes(time, Cplasma)) +
geom_line() +
geom_hline(yintercept = css) +
ylab("Plasma Concentration (uM)") +
xlab("Day") +
theme(
axis.text = element_text(size = 16),
axis.title = element_text(size = 16),
plot.title = element_text(size = 17)) +
ggtitle("Bisphenol A")
print(c.vs.t)
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