The Corrected Traditional Equations for Calculation of Hepatic Clearance that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water and the Corresponding Corrected PBPK Equation

The estimation of hepatic clearance, Cl(h), using in vitro data on metabolic stability of compound, its protein binding and blood-plasma equilibrium concentration ratio is commonly performed using well-stirred, parallel tube or dispersion models. It appears that for ionizable drugs there is a difference of the steady-state concentrations in extracelluar and intracellular water (at hepatocytes), where metabolism takes place. This occurs due to the different pH of extra- and intracellular water (7.4 and 7.0, respectively). The account of this fact leads to the novel equations for Cl(h). These equations include the additional parameter named ionization factor, F(I), which is the ratio of the unionized drug fractions in plasma and intracellular tissue water (or the ratio of the unbound drug concentrations in intracellular tissue water and plasma at equilibrium). For neutral drugs F(I) = 1 and the novel equations coincide with the traditional ones. It is shown that the account of this factor may yield the calculated Cl(h) up to 6.3-fold greater than that obtained by the traditional equations for the strong diprotic basic compounds, and up to 6.3-fold smaller for the strong diprotic acidic compounds. For triprotic acids and bases the difference could be as much as 15-fold. The account of pH difference between extra- and intracellular water also results in the change of the term commonly used to describe drug metabolic elimination rate in physiologically based pharmacokinetic (PBPK) equation. This consequently may lead to a noticeable change of drug concentration-time profiles in plasma and tissues. The effect of ionization factor is especially pronounced for the low-extraction ratio drugs. The examples of significant improvement in the prediction of hepatic clearance due to the account of ionization factor are provided. A more general equation for hepatic clearance, which accounts for ionization factor and possible drug uptake and efflux, is obtained. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1167-1183, 2011