R: Calculate the correction for lipid binding in plasma binding...

calc_fup_correction {httk}

R Documentation

Calculate the correction for lipid binding in plasma binding assay

Description

Poulin and Haddad (2012) observed "...that for a highly lipophilic compound, the calculated f_up is by far [less than] the experimental values observed under in vitro conditions." Pearce et al. (2017) hypothesized that there was additional lipid binding in vivo that acted as a sink for lipophilic compounds, reducing the effective f_up in vivo. It is possible that this is due to the binding of lipophilic compounds on the non plasma-side of the rapid equilibrium dialysis plates (Waters et al., 2008). Pearce et al. (2017) compared predicted and observed tissue partition coefficients for a range of compounds. They showed that predictions were improved by adding additional binding proportional to the distribution coefficient D_ow (calc_dow) and the fractional volume of lipid in plasma (F_lipid). We calculate F_lipid as the sum of the physiological plasma neutral lipid fractional volume and 30 percent of the plasma neutral phospholipid fractional volume. We use values from Peyret et al. (2010) for rats and Poulin and Haddad (2012) for humans. The estimate of 30 percent of the neutral phospholipid volume as neutral lipid was used for simplictity's sake in place of our membrane affinity predictor. To account for additional binding to lipid, plasma to water partitioning (K_plasma:water = 1/f_up) is increased as such: K^corrected_plasma:water = 1/f^corrected_up = 1/f^{in vitro}_up + D_ow*F_lipid

Usage

calc_fup_correction(
  fup = NULL,
  chem.cas = NULL,
  chem.name = NULL,
  dtxsid = NULL,
  parameters = NULL,
  Flipid = NULL,
  plasma.pH = 7.4,
  dow74 = NULL,
  species = "Human",
  default.to.human = FALSE,
  force.human.fup = FALSE,
  suppress.messages = FALSE
)

Arguments

`fup`	Fraction unbound in plasma, if provided this argument overides values from argument parameters and `chem.physical_and_invitro.data`
`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
`Flipid`	The fractional volume of lipid in plasma (from `physiology.data`)
`plasma.pH`	pH of plasma (default 7.4)
`dow74`	The octanol-water distribution ratio (DOW).
`species`	Species desired (either "Rat", "Rabbit", "Dog", "Mouse", or default "Human").
`default.to.human`	Substitutes missing fraction of unbound plasma with human values if true.
`force.human.fup`	Returns human fraction of unbound plasma in calculation for rats if true. When species is specified as rabbit, dog, or mouse, the human unbound fraction is substituted.
`suppress.messages`	Whether or not the output message is suppressed.

Details

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

Value

A numeric fraction unpbound in plasma between zero and one

Author(s)

John Wambaugh

References

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.

Peyret T, Poulin P, Krishnan K (2010). “A unified algorithm for predicting partition coefficients for PBPK modeling of drugs and environmental chemicals.” Toxicology and applied pharmacology, 249(3), 197–207.

Poulin P, Haddad S (2012). “Advancing prediction of tissue distribution and volume of distribution of highly lipophilic compounds from a simplified tissue-composition-based model as a mechanistic animal alternative method.” Journal of pharmaceutical sciences, 101(6), 2250–2261.

Schmitt W (2008). “General approach for the calculation of tissue to plasma partition coefficients.” Toxicology in vitro, 22(2), 457–467.

Waters, Nigel J., et al. "Validation of a rapid equilibrium dialysis approach for the measurement of plasma protein binding." Journal of pharmaceutical sciences 97.10 (2008): 4586-4595.