Drug absorption and permeability

Hou, T., Wang, J Zhang, W Wang, W. and Xu, X. (2006) Recent advances in computational prediction of drug absorption and permeability in drug discovery. Current Medicinal Chemistry, 13, 2653-2667. 

Fig. 7.5. The Biopharmaceutics Classification System (BCS) provides a scientific basis for predicting intestinal drug absorption and for identifying the rate-limiting step based on primary biopharmaceutical properties such as solubility and effective intestinal permeability (Pefr). BCS serves as a product control instrument. The BCS divides drugs into four different classes based on their solubility and...

The genesis of in silico oral bioavailability predictions can be traced back to Lip-inski s Rule of Five and others qualitative attempts to describe drug-like molecules [13-15]. These processes are useful primarily as a qualitative tool in the early stage library design and in the candidate selection. Despite its large number of falsepositive results, Lipinski s Rule of Five has come into wide use as a qualitative tool to help the chemist design bioavailable compounds. It was concluded that compounds are most likely to have poor absorption when the molecular weight is >500, the calculated octan-l-ol/water partition coefficient (c log P) is >5, the number of H-bond donors is >5, and the number of H-bond acceptors is >10. Computation of these properties is now available as an ADME (absorption, distribution, metabolism, excretion) screen in commercial software such as Tsar (from Accelrys). The rule-of-5 should be seen as a qualitative, rather than quantitative, predictor of absorption and permeability [16, 17]. 

This volume gives an overview of the current status and an outlook to future more reliable predictive approaches. It is subdivided in five sections dealing with studies of membrane permeability and oral absorption, drug dissolution and solubility, the role of transporters and metabolism in oral absorption, computational approaches to drug absorption and bioavailability, and finally with certain drug development issues. 

Smith PL (1996) Methods for evaluating intestinal permeability and metabohsm in vitro. In Borchardt RT, Smith PL, Wilson G (eds.) Models for Assessing Drug Absorption and Metabohsm. Plenum Press, New York, pp 13-34... 

Bergstrom CAS (2005) In silico predictions of drug solubility and permeability two rate-limiting barriers to oral drug absorption. Basic Clin Pharmacol Toxicol 96 156-161. 

Volpe DA, Moller H, Yu LX (2002) Regulatory acceptance of in vitro permeability studies in the context of the biopharmaceutics classification system. In Lehr CM (ed.) Cell Culture Models of Biological Barriers In Vitro Test Systems for Drug Absorption and Delivery. Taylor Francis Publishing Group, London New York, pp. 130-139. 

To maximize the chances of success, it is necessary to build in drug-like properties. One of the drug-like criteria adopted is the Lipinski Rule of 5 — so named because of its emphasis on the number 5 and multiples of 5. The rule states that potential drug candidates are likely to have poor absorption and permeability if they have ... 

Abstract This chapter attempts to give an overview on the properties of the intestinal epithelium with regard to both, barriers to transcellular (transporter and efflux systems) and paracellular (tight junctional complex) drug absorption and transport systems and tight junction modulation. A short introduction into the relation between the innate immune system and modulation of paracellular permeability is equally given. 

Although the pH-partition hypothesis relies on a quasi-equilibrium transport model of oral drug absorption and provides only qualitative aspects of absorption, the mathematics of passive transport assuming steady diffusion of the un-ionized species across the membrane allows quantitative permeability comparisons among solutes. As discussed in Chapter 2, (2.19) describes the rate of transport under sink conditions as a function of the permeability P, the surface area A of the membrane, and the drug concentration c (t) bathing the membrane ... 

Although various computational approaches for the prediction of intestinal drug permeability and solubility have been reported [219], recent computer-based absorption models utilize a large number of topological, electronic, and geometric descriptors in an effort to take both aqueous drug solubility and permeability into account. Thus, descriptors of partitioned total surface areas [168], Abraham molecular descriptors [220,221], and a variety of structural descriptors in combination with neural networks [222] have been shown to be determinants of oral drug absorption. 

While the presence of surfactants is advantageous due to an increase in cellular membrane permeability, which facilitates drug absorption and bioavailability [218], caution needs to be taken in relation to the amount of surfactant incorporated, as high concentrations can lead to ocular toxicity. In general, nonionic surfactants are preferred over ionic ones, which are generally too toxic to be used in ophthalmic... 

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