The Challenges of Predicting Toxicity

There are many challenges that have to be overcome before one can accurately predict the toxicity of a novel chemical structure. Fundamental issues, such as the complex nature of biological systems and the ability of chemicals to interact with a biological system in multiple ways that could all potentially manifest themselves as similar toxic events, inevitably mean that the problem of predicting toxicity is not straightforward. The diverse types of information that relate to the...

Roles of Transporters in Pharmacokinetics

Transporters are now recognized to be as important as the metabolizing enzymes in the modulation of the main steps controlling the fate and action of xenobiotics in the body. They affect all the main pharmacokinetic events, such as the oral bioavailability, distribution, and clearance of any substrates. As most drugs, toxicants, and carcinogens are taken orally, we focus here on their impact on the enterocytes, as these are the main intestinal cells involved in the passage of compounds from the...

Permeation Theory and In Vivo Extrapolation

5.19.3.1.1 The solubility-diffusion model for a homogeneous membrane First approximation of a biological lipid membrane is a homogeneous organic solvent membrane (Figure 6).41 Fick's first law can be applied to the homogeneous membrane permeation. The passive permeation across a membrane is a diffusion process, the driving force of which is the concentration gradient across the membrane (i.e., Fick's first law). If the interfacial resistance at the lipid-water interface is assumed to be...

Info

Figure 24 The metabolic pathway from arene oxides (74) to aromatic mercapturic acids (77) is presented here the first product of addition is 75, which dehydrates and aromatizes to 76 before being cleaved and N-acetylated. Also shown here is the logical pathway leading from valdecoxib (78) to its methyl sulfone conjugate (79). medicinal viewpoint since anticancer agents such as methylformamide appear to work by undergoing activation to isocyanates and then to the glutathione conjugate. An...

Alternatives to Caco2 Cells

Over the years, several alternatives to Caco-2 cells have been suggested for the assessment of drug permeability. In fact, MDCK cells, which are epithelial cells derived from dog kidney, were the first cells grown as monolayers on a permeable support,200 and were proposed as a cellular drug transport barrier as early as 1989. However, while MDCK cells were exploited as host cells for transfected transport proteins,202 it was not until later that their performance was compared with that of...

Conclusions and Strategy

The properties of the brain endothelium forming the BBB are important considerations when designing drugs to target or avoid the brain. Molecular traffic across the BBB is regulated by a combination of physical, transport, and metabolic barrier properties. Tight junctions restrict the paracellular pathway, and endothelial membrane lipids and other components determine the passive pathway across the cells. Specific uptake transport proteins and vesicular transcytotic mechanisms mediate the...

Opioid Receptor Agonists

Opioid receptors are activated by both endogenously produced peptides (known as endorphins or enkephalins)59'60 and exogenously administered opioid drugs which are among the most effective analgesics known. The opium alkaloid morphine and synthetic analogs are widely used in clinical practice for the treatment of severe pain. The opioid receptors belong to the family of G protein-coupled receptors (GPCRs), which are predominantly signaling through the Gi o transduction pathway. Four subtypes...

Effect of Salt Form

Low bioavailability is most common with oral dosage forms of poorly water-soluble' slowly absorbed drugs. More factors can affect bioavailability when absorption is slow or incomplete than when it is rapid and complete. The alteration of the pH of the formulation is the first way to solubilize acidic or basic compounds. Lin99 described the example of L-735'524' a human immunodeficiency virus (HIV) protease inhibitor. When given orally as a suspension in 0.5 methylcellulose (MC pH 6.5) its...

Epoxide hydrolases EC 3323

Epoxide hydrolases (EHs)38 catalyze the hydrolytic cleavage of oxirane rings. Because of the higher electron attracting force of the oxygen atom compared with the two carbon atoms of oxirane rings, epoxides possess two electrophilic carbon atoms, the electrophilic reactivity of which is enhanced by the tension of the three-membered oxirane ring. Depending on the influences of the rest of the molecule this can make epoxides highly cytotoxic, genotoxic, and carcinogenic. Therefore, the...

Toxification versus Detoxification

The key point is that a given species was not able to 'predict' what kind of xenobiotics it would be exposed in future since the organisms and their constituents in its environment obviously also underwent evolutionary changes. Thus, excretory systems of low specificity and hence high flexibility provided an evolutionary advantage. However, there was a price to pay for this flexibility. The low substrate specificity of the enzymes catalyzing the reactions allowing for a vast array of...

Available Data Sources

The scope of computational programs and models continues to increase as more compounds are added to bioavailability databases. Several companies specialize in providing experimentally derived libraries of information for bioavailability prediction in addition to supplying data based on high-throughput screening (HTS) (Table 4). For example, the AurSCOPE database contains drug information for over 7000 compounds collated from the literature. Bioavailability data is available for over 10 of...

Success of Predictions

Some of the various difficulties in assessing the in vitro parameters required for the extrapolation of in vivo human DDIs have already been addressed (see below). The importance of determining the accurate concentrations of both 'victim' and 'perpetrator' drugs at the active site of the in vitro enzyme has been well described.12'89 The potentially confounding extrapolation factors such as the free fraction of drug in blood, plasma, and the in vitro incubation of choice combine to demonstrate...

R

Many studies have focused on the substrate selectivity of potential antitumor quinones in being reduced by DT-diaphorase (NAD(P)H quinone oxidoreductase, NQO1), an enzyme over-expressed in some tumor types. And, indeed, sufficiently fast reduction by purified NQO1 and in NQO1-rich cells is a criterion of screening. However, bioreduction under hypoxic conditions also appears as a favorable feature. Good substrate selectivity toward NQO1 is exemplified by two compounds of structure 70 in (R1...

Profesor Bosterling

The Metabolism of Drugs and Other Xenobiotics - Biochemistry of RedoxReactions Academic Press London, UK, 1995. 2. Nelson, D. R. Strobel, H. W Mol. Biol. Evol. 1987, 4, 572-593. 3. Nelson, D. R. Koymans, L. Kamataki, T. Stegeman, J. J. Feyereisen, R. Waxman, D. J. Waterman, M. R. Gotoh, O. Coon, M. J. Estabrook, R. W et al. Pharmacogenetics 1996, 6, 1-42. 4. Nebert, D. W Adesnik, M. Coon, M. J. Estabrook, R. W Gonzalez, F J. Guengerich, F P Gunsalus, I. C. Johnson, E. F Kemper, B....

Cyp3a4

Constitutively very low in liver Liver Polycyclic aromatic hydrocarbons (PAH) Aromatic amines, PAH, aflatoxin B1, phenacetin, acetaminophen, caffeine, warfarin, imipramine 6-Aminochrysene, aflatoxin B1, nitrosamines, coumarin Cyclophosphamide, nicotine Diclofenac, ibuprofen, phenytoin, tolbutamide Debrisoquin, propranolol, dextromethorphan Ethanol, benzene, dimethylnitrosamine, chlorzoxazone Aflatoxin B1> acetaminophen, benzphetamine, nifedipine, steroid hormones, erythromycin Orthologous...

Conclusion

There are presently a multitude of in silico methods available for the prediction of solubility. Methods representing very different modeling approaches apparently perform well within their domain of applicability, which, however, in most cases covers only a limited volume of the druglike structure space. Improving accuracy and applicability seems to require more consideration of the consistency of the experimental solubility data and the training set composition, although advances in structure...

Conclusions and Guidelines

That log P is an important property for 'drug design' is without doubt and that it can be calculated with reasonable accuracy for many different chemical structures is also without doubt. The importance of lipophilicity prediction remains the focus of interest of many researchers who are concerned with its measurement and calculation and this can be seen by the series of conferences on log P held in Lausanne and Zurich in 1995, 2000, and 2004. Similarly, the steadily rising number of...

Bcrp Mxr Abcp

Neutral and basic amphiphatic xenobiotics Bile salts, paclitaxel, vinblastine Primary, ATP Organic anions Primary, ATP, GSH GSH and GSH-, Gluc-, Sulf-conjugates Anticancer drugs and neutral xenobiotics Organic anions, GSH and other Primary, ATP, GSH conjugates similar to MRP1 GSH and other conjugates similar to MRP1 bile acids analogues and organic anions Cyclic nucleotides, nucleoside analogues, and anionic conjugates Mitoxantrone, prazosin, topotecan, irinotecan, gleevec, flavopiridol...

Quantitative Structure Activity Relationships

Ligand-based approaches have been extensively applied to understanding SARs of hERG channel blockers. One of the earliest SAR studies performed on a series of compounds that cause QT prolongation is by Morgan and Sullivan.45 In an overview of Class III antiarrhythmic agents, the authors proposed a general structure of Q-Phenyl-A-NR1R2. R1 and R2 are preferentially hydrophobes, R1 as alkyl or phenylalkyl (R1 H is also acceptable for inclusion in the class), and R2 as alkyl, arylalkyl, or...

Pulmonary Route

The inhalation route has been developed primarily for the treatment of respiratory disorders that today affect two hundred million people worldwide. Pulmonary drug administration allows locally acting drugs to be administered directly to their site of action such as asthma and chronic obstructive pulmonary disease COPD treatments. More recently, pulmonary drug delivery has gained interest for the administration of systemic drugs, due to the large absorptive surface of the lung, the high...

References

W Human Biochemistry, 10th ed. C. V Mosby Co St. Louis, MO, 1982. 2. da Silva, C. O. da Silva, E. C. Nascimento, M. A. C. Chem. Phys. Lett. 2003, 381, 244-245. 3. Pliego, J. R., Jr. Chem. Phys. Lett. 2003, 367, 145-149. 4. Pliego, J. R., Jr. Chem. Phys. Lett. 2003, 381, 246-247. 5. Liptak, M. D. Shields, G. C. Int. J. Quantum Chem. 2001, 85, 727-741. 6. Topsom, R. D. Prog. Phys. Org. Chem. 1990, 17, 107-120. 7. Perrin, D. D. Dempsey, B. Serjeant, E. P pKa Prediction...

In Vitro Models for Plasma Binding and Tissue Storage

P Barton, R P Austin, and R E Fessey, AstraZeneca R amp D Charnwood, Loughborough, UK 2007 Elsevier Ltd. All Rights Reserved. 5.14.1 Plasma Protein Binding 322 5.14.1.2 Biological Aspects 322 5.14.1.3 Effect of Plasma Protein Binding on Drug Disposition 322 5.14.1.4 Influence of Blood Plasma Ratio on Pharmacokinetic Parameters 324 5.14.1.5 Drug-Drug Interactions 325 5.14.2 Experimental Aspects 325 5.14.2.1 Scales of Measurement of Plasma Protein Binding 325 5.14.2.2 Experimental Methods for...

Structural Factors that Modify pKa Values

The pKa values of ionizable groups are influenced by other structural factors in the molecule, as illustrated in Table 3. They comprise inductive, electrostatic, and electron delocalization mesomeric effects, together with contributions from hydrogen bonding, conformational differences, and steric factors. Electrical work is required to remove a proton from an acidic center and transfer it to a solvent molecule, or to remove a proton from a solvent molecule and transfer it to a basic center....

Ionizable Groups

This section reviews the most common ionizable groups, and the structural factors that influence pKa values. 5.16.2.1 The Number of Ionizable Drugs To evaluate their ionization properties, compounds can be divided into several classes. Some compounds are neutral nonionizable they will not be discussed in this chapter. Most ionizable compounds are acids or bases with one, two or more ionizable groups. Another class includes ampholytes and zwitterions, which are molecules with at least one acidic...

Factorization of Lipophilicity

Lipophilicity expressed as log P is a molecular parameter encoding both electrostatic and hydrophobic intermolecular forces as well as intramolecular interactions Table 2 , as shown by eqn 11 , discussed in its original form some where v is a constant, V is the molar volume which assesses the solute's capacity to elicit nonpolar interactions i.e., hydrophobic forces, and to some extent dispersive and repulsive forces , L accounts for the polarity of the molecule, I accounts for ionic...

Other Connections between pKa and Drugs

Ionization is important in the chemical analysis of drugs by high-performance liquid chromatography, because ionized and unionized forms of molecule behave quite differently in chromatographic systems.39,40 As well as its influence on gastrointestinal absorption, ionization is important in the transport and disposition of drugs in other organs and biological fluids. For example, it is noted that in the treatment of diseases of the prostate, the tissues are best penetrated by antimicrobial drugs...

Terminology pH Scale and pKa Definitions

This section introduces the terminology of pH and ionization, as a well as equations for calculating the pH of solutions of weak acids and bases, and for plotting distribution of species profiles. It also introduces ampholytes and zwitterions, and the concept of protonation microconstants. This chapter is concerned only with acid-base ionizations of organic molecules involving the gain or loss of hydrogen ions this is the main class of ionization that can occur in solution. The terminology for...

Ionization and Lipophilicity

Molecules are most lipophilic when they are unionized, and their lipophilicity decreases rapidly when they are ionized. This has an important implication for the absorption and transport of drugs as a result of their permeability by passive diffusion through membranes and lipid bilayers. Figure 14 shows the lipophilicity expressed as octanol water partition of three ionizable drugs as a function of pH. Significant variations in lipophilicity occur over the physiological pH range. The pH of...

PH Gradient Titration

A technique called pH gradient titration can be used for the rapid measurement of pKa. In this technique, samples are injected into a flowing pH gradient, which is created by mixing an acidified and a basified linear buffer together using syringe pumps running at inversely varying speeds. During the gradient the pH varies linearly, and the pH at any given time may be predicted from the time elapsed since the start of gradient generation. This eliminates the need for pH measurement, which is one...