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#' Correct the measured intrinsive hepatic clearance for fraction free
#'
#' This function uses the free fraction estimated from Kilford et al. (2008)
#' to increase the in vitro measure intrinsic hepatic clearance. The assumption
#' that chemical that is bound in vitro is not available to be metabolized and
#' therefore the actual rate of clearance is actually faster. Note that in most
#' high throughput TK models included in the package this increase is offset by
#' the assumption of "restrictive clearance" -- that is, the rate of hepatic
#' metabolism is slowed to account for the free fraction of chemical in plasma.
#' This adjustment was made starting in Wetmore et al. (2015) in order to better
#' predict plasma concentrations.
#'
#' @param Clint In vitro measured intrinsic hepatic clearance in units of
#' (ul/min/million hepatocytes).
#'
#' @param Fu_hep Estimated fraction of chemical free for metabolism in the
#' in vitro assay, estimated by default from the method of Kilford et al. (2008)
#' using \code{\link{calc_hep_fu}}
#'
#' @param Pow The octanal:water equilibrium partition coefficient
#'
#' @param pKa_Donor A string containing hydrogen donor ionization equilibria,
#' concatenated with commas. Can be "NA" if none exist.
#'
#' @param pKa_Accept A string containing hydrogen acceptance ionization equilibria,
#' concatenated with commas. Can be "NA" if none exist.
#'
#' @param suppress.messages Whether or not the output message is suppressed.
#'
#' @return Intrinsic hepatic clearance increased to take into account binding
#' in the in vitro assay
#'
#' @author John Wambaugh
#'
#' @references
#' Kilford, Peter J., et al. "Hepatocellular binding of drugs:
#' correction for unbound fraction in hepatocyte incubations using microsomal
#' binding or drug lipophilicity data." Drug Metabolism and Disposition 36.7
#' (2008): 1194-1197.
#'
#' Wetmore, Barbara A., et al. "Incorporating high-throughput exposure
#' predictions with dosimetry-adjusted in vitro bioactivity to inform chemical
#' toxicity testing." Toxicological Sciences 148.1 (2015): 121-136.
#'
#' @keywords in-vitro
#'
#' @seealso \code{\link{calc_hep_fu}}
#'
#' @export apply_clint_adjustment
apply_clint_adjustment <- function(Clint,
Fu_hep=NULL,
Pow = NULL,
pKa_Donor=NULL,
pKa_Accept=NULL,
suppress.messages=FALSE)
{
if (is.null(Fu_hep))
{
Fu_hep <- calc_hep_fu(parameters=list(Pow = Pow,
pKa_Donor = pKa_Donor,
pKa_Accept = pKa_Accept))
}
Clint <- Clint / Fu_hep
if (!suppress.messages)
{
warning('Clint adjusted for in vitro partitioning (Kilford, 2008), see calc_hep_fu.')
}
return(set_httk_precision(Clint))
}
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