Homology Modeling of Human Etheragogo Related Gene

At least two groups33'34 have reported hERG homology models using available atomic resolution structures of bacterial K+ channels KcsA35 (closed) and MthK36 (open). These channels contain only two transmembrane domains (equivalent to helices S5 S6 in Figure 3), and the models therefore only cover the predicted structure of the hERG pore. The basic architecture of hERG channel is expected to be similar to that of other voltage-gated K+ channels, such as KvAP (Figure 3).37 The channel pore domain...

In Silico Prediction of Carcinogenicity

Cancer is a disorder in which the mechanisms that control proliferation of cells no longer function adequately. Cancer is considered to be an all-or-none effect (i.e., a tumor is or is not present). Because most cancers are considered irreversible life-threatening changes, chemical carcinogenesis (chemically induced cancer development) has hitherto been perceived by many to be different from other forms of chemical toxicity. Currently there are no good in vitro assays that can be used to...

Blood Brain Partitioning

Whether drug design criteria require significant brain penetration or demand minimal partitioning into brain tissue, estimation of the brain-blood ratio, BB brain blood , is essential in drug design. In our first study, we organized experimental data, given as the logarithm, log BB, from 11 literature sources to create a very diverse set of 106 compounds.28 MLR methods led to models, but the linear technique yielded poor statistics. When nonlinear terms were developed for specific structure...

Ionization and Absorption

According to the classic pH partition theory, only the uncharged species of ionizable drugs will partition into biological phases.27 Thus molecules are more permeable by passive diffusion through lipid membranes when unionized, while ionized molecules remain in aqueous phases such as blood and are more readily excreted via the kidneys. The fraction of drug absorbed may be higher than expected from pH partition theory when biological phenomena relating to membranes are taken into account. Thus,...

Si s

Figure 5 Modeling approach within drug discovery and early nonclinical development. (Reprinted from Theil, F. P. Guentert, T. W. Haddad, S . Poulin, P. Toxicol. Lett. 2003, 138, 29-49, with permission from Elsevier.) 3. Simulation prior to in vivo studies Figure 6 Application of PBPK during the drug discovery and development processes. (Reproduced with permission from Parrott, N. Jones, H. Paquereau, N. Lave, T. Basic Clin. Pharmacol. Toxicol. 2005, 96, 193-199.) 3. Simulation prior to in vivo...

Adenosine Ai Receptor Agonists

The endogenous nucleoside adenosine exerts a variety of physiological effects via interactions with a family of G protein-coupled receptors consisting of four subtypes the adenosine A A2A, A2B, and A3 receptors.49 The A1 receptor is the most comprehensively studied adenosine receptor subtype and has been cloned from a number of species, including humans. Ai receptors are believed to act mainly via the Gi o family of G proteins and are widely expressed in the brain, spinal cord and a variety of...

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...

Plasma Protein Binding

The role of plasma protein binding (PPB) in the discovery process and the impact this key parameter has on the discovery and clinical process is now becoming fully realized. The pharmacokinetic and pharmacodynamic properties of drugs are greatly influenced by the reversible binding to plasma proteins with the unbound fraction of the drug being responsible for the biological activity. Methods are now available for the rapid determination of free levels in plasma using a multitude of techniques...

Serotonin 5HT1A Receptor Agonists

A wide array of selective and less selective 5HT1A receptor ligands has been developed. It has been shown that these compounds are of value in the treatment of anxiety disorders and depression. In addition they may be of value in therapeutic indications such as aggression, addiction, seizures, nausea, and neuroprotection. The mechanism of action of 5HT1A receptor ligands is not entirely resolved. It is believed however that differences in intrinsic efficacy at 5HT1A receptors in different areas...

The Phase Concept of Drug Metabolism and Its Importance for Toxification versus Detoxification

The phase concept of drug metabolism is described elsewhere in this book (see 5.05 Principles of Drug Metabolism 1 Redox Reactions 5.06 Principles of Drug Metabolism 2 Hydrolysis and Conjugation Reactions). With respect to toxification versus detoxification it is important that depending on their chemical nature the functional groups introduced in the phase I of drug metabolism can be classified as electrophilic or nucleophilic (Figure 1). Functional groups with an electrophilic carbon are, for...

Bioprecursors and Bioreductive Agents

As defined above, bioprecursors are prodrugs containing a functional group whose biotransformation generates the active agent without release of any promoiety.1'6'7 As for carrier-linked prodrugs, the bioactivation of bioprecursors can involve a reaction of oxidation, reduction, or hydrolysis hydration. But while hydrolysis is by far the most frequent mechanism of activation of the carrier-linked prodrugs, a majority of known bioprecursors are activated by reduction. A further difference...

Scope of Drug Metabolism toward Xenobiotic Detoxification

Over the course of evolution organisms were exposed to environmental compounds of negligible nutritive value. These have variably been called 'foreign compounds' or 'xenobiotics.' Also the term 'drug' is used for them in contrast to the narrower term 'therapeutic drug' to specifically designate those xenobiotics that are intended for clinical use. Organisms that developed systems enabling them to get rid of these xenobiotics before they could accumulate to toxic levels had an evolutionary...

Modeling of Phase 2 Metabolism Enzymes

Whereas Phase 1 metabolism involves hydroxylation, oxidation, and reduction pathways, phase 2 metabolism involves primarily conjugation (of the phase 1 metabolites) with a variety of groups (e.g., sulfation, glucuronidation, glutathione conjugation, acetylation, amino acid conjugation, and methylation).67 With the exceptions of methylation and acetylation, phase 2 biotransformation reactions result in a large increase in hydrophilicity.68 Enzymes involved in phase 2 metabolism include, GST, MT,...

RCH2NR2R3 O2 H2O rcho hnr2r3 H2O2

The hydrogen peroxide formed can reach toxicologically relevant levels. (MPTP) is an interesting example of metabolism-related selective toxicity. It is toxified via the intermediate 1-methyl-4-phenyl-2,3-dihydropyridinium salt (MPDP +) to the 1-methyl-4-phenyl pyridinium salt (MPP+). MPP+ is taken up by a high-affinity reuptake system specifically localized in the nigrostriatal dopaminergic neurons and blocks their mitochondrial energy metabolism. This leads to death of these neurons, which...

Buccal Route

Buccal administration is intended for delivering drugs within through the buccal mucosa in order to achieve a local or systemic effect. This route is particularly attractive since substances absorbed through the buccal mucosa bypass gastrointestinal enzymatic degradation and the hepatic first-pass effect. The mouth has a relatively large area for drug application and good accessibility compared to the nose, rectum, and vagina.3 In addition, the mucosa is resistant to damage or irritation...

Discussion and Conclusion

Progress in optimizing the way to carry out in vitro metabolic studies in R amp D has been constant over the last decade. In a way, xenobiotic metabolism represents a quite unique domain within R amp D. It is effectively one of the sole disciplines present at every major step in R amp D, and provides pivotal information to pharmacologists, chemists, toxicologists, and clinical scientists. It has therefore evolved toward the use of a large range of metabolic tools, allowing the rapid...

Ontogenic development

Organ maturation during fetal life and adulthood has a profound effect on the ability of that tissue to metabolize drugs.24,25 Maturation of drug-metabolizing enzymes is perhaps the major factor accounting for age-associated changes in the nonrenal clearance of drugs. Individual variability in drug metabolism during different stages of infancy, childhood, and adolescence can partially be explained by the gradual developement of drug-metabolizing enzymes, and failure to recognize this effect can...

Conclusions and Strategy

Professor Joan Abbott

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...

Breier Barancik 2012

We are grateful to the Alexander von Humboldt Foundation, DFG, DAAD, and the National Science Fund of Bulgaria for the financial support of our studies. 1. Dano, K. Biochim. Biophys. Acta. 1973, 323, 466-483. 2. Juliano, R. L. Ling, V Biochim. Biophys. Acta. 1976, 455, 152-162. 3. Gottesmann, M. M. Pastan, I. Annu. Rev. Biochem. 1993, 62, 385-427. 4. Mirski, S. E. L. Gerlach, J. H. Cole, S. P. C. Cancer Res. 1987, 47, 2594-2598. 5. Hipfner, D. R. Deeley, R. G. Cole, S. P C. Biochim. Biophys....

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...

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...

Carbonyl and quinone reductases

The carbonyl moiety of aldehydes, ketones, and quinones, often encountered in xenobiotic molecules, is the most common target of reductase enzymes, resulting in the formation of hydrophilic alcohols and hydroquinones that can readily undergo conjugation prior to excretion. This is an important biological function in that it provides a protective mechanism against a host of potentially reactive compounds that are formed intracellularly. Carbonyl-reducing enzymes belong to four main categories 1...

Info

Partition Coefficient Drugs

Transferrin Insulin Leptin Cytokines Viruses Glucose Amino acids Amines Nucleosides Monocarboxylates Small peptides Transferrin Insulin Leptin Cytokines Viruses Figure 3 Potential routes for transport across the brain endothelium forming the BBB. a Leucocytes may cross the BBB adjacent to, or by modifying, the tight junctions. b Solutes may passively diffuse through the cell membrane and cross the endothelium. Greater lipid solubility favors this process. c Active efflux carriers may intercept...

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...

Influence of Plasma Binding and Tissue Binding on Volume of Distribution

Volume of distribution Vss is a critical pharmacokinetic parameter that is an important component of drug in vivo halflife. The ability to generate reliable predictions of human Vss from preclinical data will frequently be a key component of the success of a drug research project. Volume of distribution can be viewed as a property that arises from the relative affinity of a compound for plasma versus tissue. Consequently, most methods for understanding and predicting Vss do so with...

Tissue distribution and ontogenic development

MAO is mainly located in the outer membrane of mitochondria of presynaptic nerve terminals, where oxidative deamination of norepinephrine, epinephrine, and serotonin by MAO inactivates these neurotransmitters and abrogates the neural stimulus. Both MAO-A and MAO-B are expressed in several human tissues, with the highest concentrations evident in liver, followed by myocardium, renal cortex, and intestine.57 MAO-A is selectively expressed in the placenta while MAO-B is selectively expressed in...

Vol Surf Descriptors

The program VolSurf derives molecular descriptors from the GRID molecular interaction fields, based on three different probes, the water H2O , the hydrophobic DRY , and the hydrogen bond acceptor O probes Figure 5 . These probes were selected since properties such as shape, electrostatics, hydrogen bonding, and hydrophobicity are known to influence the interaction of molecules with biological membranes.127 The descriptors from VolSurf are alignment independent and moderately dependent on the...

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...

Arene oxide substrates

Together with glutathione conjugation, hydration is a major pathway in the inactivation and detoxification of arene oxides. As a rule, these are good substrates of microsomal epoxide hydrolase. But when reading the literature, the Figure 7 A simplified model showing that the nucleophilic attack of the substrate is mediated by a carboxylate group in the catalytic site to form an ester intermediate. Only in the second step is the intermediate hydrolyzed by an activated water molecule, leading to...

In Vitro Surrogate Blood Brain Barrier Models

In spite of the documented value of cultured brain endothelial cells as BBB models, they have not been universally popular with pharmaceutical companies. This is largely due to the labor-intensive nature of their preparation, and the fact that the expertise needed to prepare reproducible cultures is greater than for commonly used epithelial models such as Caco-2 and MDCK. These are widely used as assay systems to predict gastrointestinal permeability of a compound or drug see 5.11 Passive...

Dilikor U Pirot

Control. Release 1985, 2, 257-275. 2. Peppas, N. A. Int. J. Pharm. 2004, 277, 11-17. 3. Rathbone, M. J. Drummond, B. K. Tucker, I. G. Adv. Drug Deliv. Rev. 1994, 13, 1-22. 4. Squier, C. A. Wertz, P W Structure and Function of the Oral Mucosa and Implications for Drug Delivery. In Oral Mucosal Drug Delivery Rathbone, M. J., Ed. Marcel Dekker New York, 1996, pp 1-26. 5. Squier, C. A. Hall, B. K. Arch. Oral Biol. 1985, 30, 485-491. 6. De Vries, M. E. Bodde, H. E....

Structure

Cyp2a6 Orientation Endoplasmic Reticulum

In general, P450s are 450-500-amino-acid 55-60 kDa proteins with a completely conserved C-terminal cysteine residue that provides the thiolate coordinate bond to the iron atom which tethers the heme prosthetic group. Intracellularly, P450s reside in the soluble fraction of the cell bacterial enzymes , the inner membrane of the mitochondrion several steroid-metabolizing P450s , or the endoplasmic reticulum drug-metabolizing P450s targeting is dependent on the nature of the N-terminal leader...

Routes Across the Blood Brain Barrier

Rmt Receptor Mediated Transcytosis

For drug discovery programs involving compounds designed to target or avoid the central nervous system CNS , several potential routes for permeation across the BBB are relevant.1,8,9 The brain endothelial tight junctions severely restrict the penetration of hydrophilic solutes via the intercellular cleft paracellular pathway , forcing molecular traffic between blood and brain to take a largely transcellular route Figure 3 .2,3 Gaseous molecules such as O2 and CO2, and small lipophilic agents,...

Dehydrogenases and reductases

Alcohol dehydrogenase E.C. 1.1.1 ADH 32 toxifies ethanol to acetaldehyde, which is then predominantly detoxified by an aldehyde dehydrogenase E.C. 1.2.1 to acetic acid. The second step, the aldehyde dehydrogenase-mediated oxidation to acetic acid, is inhibited by disulfiram Antabus , which is used in the treatment of alcohol addiction. After alcohol consumption disulfiram leads to the accumulation of the toxic acetaldehyde. The resulting toxicity provokes headache and nausea, which is intended...

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...

UDPglucuronosyltransferases EC 24117

Conjugation with glucuronic acid is the most abundant phase-II reaction see 5.06 Principles of Drug Metabolism 2 Hydrolysis and Conjugation Reactions . UDP-glucuronosyltransferases UGTs 52 catalyze the formation of beta-D-glucuronides from a large variety of xenobiotics by their reaction with UDP-glucuronic acid UDPGA . Hydroxyl-, thiol-, amino-, hydroxylamino- and carboxyl-substituents serve as the anchor to which glucuronic acid can be conjugated also C-glucuronides can be formed if the...

Passive Transcellular Transport

The passive transcellular pathway is still by far the most important absorption pathway for drugs. Drug transport via the passive transcellular route requires that the solute permeates the apical cell membrane. The composition of the phospholipids and proteins of the cell membranes varies from cell type to cell type, and may, theoretically, give rise to different permeability properties depending on the cell type. In addition, monolayer-forming cells such as the intestinal enterocytes have a...

Pka Of Clioquinol

Ampicilline Pka

Figure 3 Distribution of species of clioquinol, an ampholyte with base pKa 2.96 and acid pKa 7.60. Clioquinol is unionized at intestinal pH. Figure 3 Distribution of species of clioquinol, an ampholyte with base pKa 2.96 and acid pKa 7.60. Clioquinol is unionized at intestinal pH. Figure 4 Distribution of species of ampicillin, a zwitterion with base pKa 7.14 and acid pKa 2.55. Ampicillin is ionized across the entire pH range. Figure 4 Distribution of species of ampicillin, a zwitterion with...

Ionization and Lipophilicity

Ibuprofen Ionisable Form

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...

Alkene oxide substrates

Drug Metabolism

Alkene oxides are generally quite stable chemically, indicating a much reduced chemical reactivity compared to arene oxides. Under physiologically relevant conditions, they have little capacity to undergo rearrangement reactions and are resistant to uncatalyzed hydration. As a result, many alkene oxides formed as metabolites are stable enough to allow their isolation in the absence of degrading enzymes. Some drugs contain an unconjugated alkene group undergoing CYP-catalyzed epoxidation...

Substrates of methyltransferases

Figure 10 also shows the main methylation reactions seen in drug metabolism. O-Methylations Figure 10a are common reactions of compounds containing a catechol moiety, with a usual regioselectivity for the meta position. The substrates can be xenobiotics and particularly drugs, l-DOPA being a classic example. More frequently, however, O-methylation occurs as a late event in the metabolism of aryl groups, after they have been oxidized to catechols see Figure 8 . This sequence was seen, for...

Other hydrolases

Glycosidases and sulfatases are further hydrolases of importance for drug metabolism. They primarily metabolize endogenous substrates including glycosaminoglycans and steroids, but they also accept some xenobiotic substrates this is particularly true for the beta-glucuronidases. The gut flora can deconjugate compounds that are excreted via the bile as glucuronides or sulfates. The deconjugation products are often reabsorbed from the gut leading to enterohepatic circulation. Frequently, the...

Cyp3a4

Dihydrodiol Epoxide

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

The Why and How of Absorption Distribution Metabolism Excretion and Toxicity Research

Lead Distribution Excretion

H Van de Waterbeemd, AstraZeneca, Macclesfield, UK B Testa, University Hospital Centre, Lausanne, Switzerland 2007 Elsevier Ltd. All Rights Reserved. 5.01.1 Evolving Paradigm in Drug R amp D 1 5.01.2 The Increasing Role of Absorption, Distribution, Metabolism, Excretion, and Toxicity ADME-Tox in Pharmaceutical R amp D 3 5.01.2.1 Issues in Absorption, Distribution, Metabolism, Excretion, and Toxicity 3 5.01.2.1.2 Metabolite identification 4 5.01.2.1.3 Drug-Drug interactions 4 5.01.2.1.4...

References

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....

Amino acid conjugation

Benzoic Acid Conjugation With Glycine

Amino acid conjugation is a significant metabolic route for a number of carboxylic acids and involves the formation of an amide bond between the xenobiotic acyl-CoA and the amino acid. Glycine is the amino acid most frequently used for conjugation of small aromatic acids reaction A in Figure 19 , while a few glutamine conjugates reaction B in Figure 19 have been characterized in humans. In addition, taurine reaction C in Figure 19 and perhaps a few other amino acids and dipeptides can be used...

Cooh

Figure 6 Topological models of the human SLC22 a organic cation transporters OCT , organic anion transporters OAT , and SLCO b the organic anion polypeptide transporter OATP . Features common to all members of the OCT, OAT, OATP transporter family include 12 transmembrane-spanning domains TMDs with intracellular amino and carboxyl termini. Transmembrane a-helical domains TMD indicated by red rectangular bars N-glycosylation sites indicated by branches are present on extracellular protein loops....

Roles of Transporters in Pharmacokinetics

Abc Slc Transporters

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...

Comprehensive Medicinal Chemistry II Volume 5 ADMETox Approaches

Taylor and David J. Triggle 5.01 The Why and How of Absorption, Distribution, Metabolism, Excretion, and Toxicity Research, Pages 1-9, H. Van de Waterbeemd and B. Testa Biological and In Vivo Aspects of Absorption, Distribution, Metabolism, Excretion, and 5.02 Clinical Pharmacokinetic Criteria for Drug Research, Pages 11-30, J.-P. Tillement and D. Tremblay 5.03 In Vivo Absorption, Distribution, Metabolism, and Excretion Studies in Discovery and Development, Pages 31-50,...