Crosstalk of physiological pH and chemical pKa under the umbrella of physiologically based pharmacokinetic modeling of drug absorption, distribution, metabolism, excretion, and toxicity

Introduction: Physiological pH and chemical pKa are two sides of the same coin in defining ionization a drug human body. The Henderson-Hasselbalch equation pH-partition hypothesis form theoretical base to define impact pH-pKa crosstalk on thence its absorption, distribution, metabolism, excretion, toxicity (ADMET).Areas covered: Human physiological is not constant, but diverse, dynamic state regulated by various biological mechanisms, while generally constant acidic dissociation at environmental pH. Works scattered literature, despite significant contributions pharmacokinetics, pharmacodynamics, safety, toxicity. In particular, impacts ADMET have been effectively linked physiologically based pharmacokinetic (PBPK) modeling simulation, powerful tool increasingly used model-informed development (MIDD).Expert opinion: Lacking full consideration interactions PBPK model limits scientists’ capability mechanistically describing ADMET. This mini-review compiled literature knowledge ADMET, from viewpoint modeling, pave way systematic incorporation into simulation.