R: Calculate the free chemical in the hepaitic clearance assay

calc_hep_fu {httk}

R Documentation

Calculate the free chemical in the hepaitic clearance assay

Description

This function uses the method from Kilford et al. (2008) to calculate the fraction of unbound chemical in the hepatocyte intrinsic clearance assay. The bound chemical is presumed to be unavailable during the performance of the assay, so this fraction can be used to increase the apparent clearance rate to better estimate in vivo clearance. For bases, the fraction of chemical unbound in hepatocyte clearance assays (fu_hep) is calculated in terms of logP_ow but for neutrual and acidic compounds we use logD_ow (from calc_dow). Here we denote the appropriate partition coefficient as "logP/D". Kilford et al. (2008) calculates fu_hep = 1/(1 + 125*V_R*10^(0.072*logP/D² + 0.067*logP/D-1.126))

Usage

calc_hep_fu(
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  parameters = NULL,
  Vr = 0.005,
  pH = 7.4
)

Arguments

`chem.cas`	Chemical Abstract Services Registry Number (CAS-RN) – if parameters is not specified then the chemical must be identified by either CAS, name, or DTXISD
`chem.name`	Chemical name (spaces and capitalization ignored) – if parameters is not specified then the chemical must be identified by either CAS, name, or DTXISD
`dtxsid`	EPA's 'DSSTox Structure ID (https://comptox.epa.gov/dashboard) – if parameters is not specified then the chemical must be identified by either CAS, name, or DTXSIDs
`parameters`	Parameters from the appropriate parameterization function for the model indicated by argument model
`Vr`	Ratio of cell volume to incubation volume. Default (0.005) is taken from
`pH`	pH of the incupation medium.

Details

Note that octanal:water partitioning above 1:1,000,000 (LogP_ow > 6) are truncated at 1:1,000,000 because greater partitioning would likely take longer than hepatocyte assay itself.

Value

A numeric fraction between zero and one

Author(s)

John Wambaugh and Robert Pearce

References

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.

Wetmore BA, Wambaugh JF, Allen B, Ferguson SS, Sochaski MA, Setzer RW, Houck KA, Strope CL, Cantwell K, Judson RS, others (2015). “Incorporating high-throughput exposure predictions with dosimetry-adjusted in vitro bioactivity to inform chemical toxicity testing.” Toxicological Sciences, 148(1), 121–136.