calc_hep_clearance {httk}R Documentation

Calculate the hepatic clearance.

Description

This function calculates the hepatic clearance in plasma for using the "well-stirred" model by default. Other scaling options from (Ito and Houston 2004) are also available. Parameters for scaling from flow-free intrinsic-hepatic clearance to whole-liver metabolism rate are taken from (Carlile et al. 1997). In vitro measured hepatic clearace is corrected for estimated binding in the in vitro clearance assay using the model of (Kilford et al. 2008). The agument restrictive.clearance (defaults to TRUE) describes the significance (or lack thereof) of plasma protein binding in metabolism. Restrictive clearance assumes that only the free fraction of chemical in plasma is available for metabolism. Non-restrictive clearance assumes that the compound is weakly bound to plasma protein and any free chemical metabolized is instantly replaced. For non-restrictive clearance the effective fup = 1.

Usage

calc_hep_clearance(
  chem.name = NULL,
  chem.cas = NULL,
  dtxsid = NULL,
  parameters = NULL,
  hepatic.model = "well-stirred",
  suppress.messages = FALSE,
  well.stirred.correction = TRUE,
  restrictive.clearance = TRUE,
  species = "Human",
  adjusted.Funbound.plasma = TRUE,
  ...
)

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_steadystate function, overrides chem.name and chem.cas.

hepatic.model

Model used in calculating hepatic clearance, unscaled, parallel tube, dispersion, or default well-stirred.

suppress.messages

Whether or not to suppress the output message.

well.stirred.correction

Uses the (Yang et al. 2007) blood:plasma ratio correction in the calculation of hepatic clearance for well-stirred model if TRUE if argument hepatic.model = "well-stirred".

restrictive.clearance

If TRUE (default) the rate of metabolism is restricted to the unbound fraction of chemical. If FALSE the free fraction is set to 1 (that is, plasma protein binding is weak and metabolzied chemical is rapidly replaced)

species

Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human").

adjusted.Funbound.plasma

Uses the (Pearce et al. 2017) lipid binding adjustment for Funbound.plasma (which also impacts partition coefficients such as blood:plasma ratio) when set to TRUE (Default).

...

Additional parameters passed to parameterize_steadystate if parameters is NULL.

Value

Hepatic Clearance

Units of L/h/kg BW.

Author(s)

John Wambaugh and Robert Pearce

References

Carlile DJ, Zomorodi K, Houston JB (1997). “Scaling factors to relate drug metabolic clearance in hepatic microsomes, isolated hepatocytes, and the intact liver: studies with induced livers involving diazepam.” Drug metabolism and disposition, 25(8), 903–911.

Ito K, Houston JB (2004). “Comparison of the use of liver models for predicting drug clearance using in vitro kinetic data from hepatic microsomes and isolated hepatocytes.” Pharmaceutical research, 21, 785–792. doi:10.1023/B:PHAM.0000026429.12114.7d.

Kilford PJ, Gertz M, Houston JB, Galetin A (2008). “Hepatocellular binding of drugs: correction for unbound fraction in hepatocyte incubations using microsomal binding or drug lipophilicity data.” Drug Metabolism and Disposition, 36(7), 1194–1197. doi:10.1124/dmd.108.020834.

Pearce RG, Setzer RW, Davis JL, Wambaugh JF (2017). “Evaluation and calibration of high-throughput predictions of chemical distribution to tissues.” Journal of pharmacokinetics and pharmacodynamics, 44, 549–565. doi:10.1007/s10928-017-9548-7.

Yang J, Jamei M, Yeo KR, Rostami-Hodjegan A, Tucker GT (2007). “Misuse of the well-stirred model of hepatic drug clearance.” Drug Metabolism and Disposition, 35(3), 501–502. doi:10.1124/dmd.106.013359.

Examples


calc_hep_clearance(chem.name="Ibuprofen",hepatic.model='unscaled')
calc_hep_clearance(chem.name="Ibuprofen",well.stirred.correction=FALSE)


[Package httk version 2.6.1 Index]