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Implications of In Vitro System Conditions for CYP2C9 and CYP3A4: Impact of pH on Clearance and Enzyme Inhibition

Common practice in drug discovery is to use buffer systems witha pH of 7.4 for drug metabolism and drug‐drug interaction studies despite evidence that the intracellular pH of hepatocytes is approximately 7.0. Systemp H will govern the ratio of ionized (charged) and non‐ionized (non‐charged)species for ionizable drugs. As a result of the pH gradient between the extracellular plasma and the intracellular cytosol of the hepatocyte, anunbound drug gradient, dependent on the physiochemical properties of the drug exists. An ionization correction factor [Berezhkovskiy (2011)]was proposed to account for this phenomenon when scaling in vitro findings at pH 7.4 to in vivo predictions of hepatic clearance. However, this correction ignores the potential changes in enzyme function at the lower pH environment.