Permeability - Measurement and Prediction in Drug Discovery

Membrane Permeability - Measurement and Prediction in Drug Discovery 

Kiyohiko Sugano, Lourdes Cucurull-Sanchez, and Joanne Bennett 

Membrane permeability is one of the most important determinants of pharmacokinetics, not only for oral absorption, but also for renal re-absorption, biliary excretion, skin permeation, distribution to a specific organ and so on. In addition, modification of membrane permeability by formulation is rarely successful. Therefore, membrane permeability should be optimized during the structure optimization process in drug discovery. In this chapter, we give an overview of the physiology and chemistry of the membranes, in vitro permeability models and in silica predictions. This chapter focuses on progress in recent years in intestinal and blood-brain barrier (BBB) membrane permeation. There are a number of useful reviews summarizing earlier work [1-5]. 

---

Various in vitro assays are widely available for profiling distribution, metabolism, and pharmacokinetics (DMPK, also referred to as ADME absorption, distribution, metabolism, and excretion). Such properties of molecules are measured to ultimately predict their in vivo behavior. The metabolic stability of molecules is assessed routinely in drug discovery units by way of medium- to high-through-put assays using hepatic microsomes or hepatocytes obtained from different species (usually rat and/or human). Permeability assays (e.g., utilizing Caco-2 or MDCK cells) together with an assessment of efflux potential are also useful to troubleshoot unexpectedly low cell activity or can help select candidates for subsequent in vivo studies. 

In many cases, the intended use of in vitro BBB permeability in the drug discovery process is to predict whether investigational drugs are likely to achieve relevant CNS concentration to elicit the desired pharmacological effect. However, BBB permeability is a measurement of the rate of drug delivery to the CNS (i.e., how fast compounds cross the BBB) which must be considered separately from the extent of equilibration of the drug across the BBB and the... 

The prediction of the important structural features that affect intestinal permeability is useful information to obtain early in the drug discovery process. The two most common models used to obtain fast, high-throughput measurements are the parallel artificial membrane permeation assay (PAMPA) and the cell line assays that feature cultured human colon adenocarcinoma cells (Caco-2). Each method uses a surrogate model to mimic intestinal absorption followed by LC-MS analysis. 

It must be noted that permeability and aqueous solubility are also pKa dependent. Thus in the last twenty years, the need for accurate and precise pKa values in the drug discovery process has fueled the development of methods to measure pKa values and to predict them from structure. Measurements of log D and pKa have been well addressed by Corner. For further detailed discussion of pKa values and their prediction methodologies, readers are referred to an important publication of Fraczkiewicz. A few common methods for the pKa values prediction are summarized in Table 7.1. The most commonly used programs for the pKa calculation are listed in Table 7.2. 

---