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

Automated summary

The interaction between physiological pH and chemical pKa plays a crucial role in drug ionization and its effects on absorption, distribution, metabolism, excretion, and toxicity. However, current research on this topic is fragmented. The lack of full consideration of this interaction in PBPK modeling limits scientists' ability to mechanistically describe drug ADMET.