INTEGRATED EVALUATION OF DRUG STABILITY AND PLASMA PROTEIN BINDING FOR IMPROVED PHARMACOKINETIC PREDICTION

Abstract

Although the classical approach to drug Pharmacokinetics has considered chemical and metabolic stability separately from plasma protein binding, in the biological environment these two properties are linked and exert significant mutual influences, which cannot be detected by individual assessment of the two properties. The stability of a drug can also be altered during routine binding experiments, causing the measured free fraction to be falsely high, and causing the volume of distribution, clearance, and half-life to be incorrectly determined. High affinity plasma protein binding, however, can be protective against degradation by enzymes and/or chemistry for labile drugs, depending on experimental conditions, creating a mechanistic interplay that protects or eliminates the labile drug. This article critically analyzes the comprehensive effect of drug stability and plasma protein binding on absorption, distribution, metabolism, excretion and toxicity. We show how the unbound fraction and intrinsic clearance should be corrected for degradation in the biological matrices in both in vitro experiments and ex vivo sample handling. The high plasma protein binding and the poor stability often result in false predictions of the long half-life when the degradation products are neglected. This interplay is intentionally used in the design of a number of drug classes, such as ester prodrugs and soft drugs, to obtain desirable drug properties. In this work, we suggest that the use of in vitro/ in vivo extrapolation models which take into account real-time plasma matrix stability evaluation would significantly enhance drug design and therapeutic outcomes. The following sections will summarize basic principles, discuss common experimental issues, describe mathematical models for correcting the data and offer suggestions for medicinal chemists and pharmacokinetics scientists