X

Metabolism of oxygen-containing compounds. Ethers. The P450-mediated oxidation of ethers proceeds by oxidation of the alpha carbon via HAT to form a radical, followed by a hydroxyl radical rebound. This mechanism results in the formation of a hemiacetal that hydrolyses to an alcohol and an aldehyde product. Methylenedioxybenzenes. The P450-mediated oxidation of methylenedioxybenzenes proceeds via oxidization of the methylene to a carbene (a carbon with six valence electrons)...

Chemical Nomenclature

Here we present information on the naming convention of various organic chemicals and common moieties used by medicinal chemists. We also included figures of typical five-membered, six-mem-bered and bicyclic heterocyclic rings. 12.1 General Nomenclature for Organic Compounds 201 12.1 GENERAL NOMENCLATURE FOR ORGANIC COMPOUNDS General prefix for a carbon chain of any length alkGeneral suffix for a functional group moiety -yl Table12.L Prefixes based C1 meth- C4 but- C7 hept- C10 dec-on length of...

Monoamine Oxidases MAOs EC 1434

Cellular location Outer membrane of mitochondria. Organ distribution Expressed in most tissues. Prosthetic group FAD Overall reaction 1. RCH2NH2 (substrate) + O2 RCH NH + H2O2. 2. RCH NH + H2O RCH O + NH3. The aldehyde formed is usually oxidized further to an acid or reduced to an alcohol by other enzymes (see Table 2.11). Isoforms MAO-A and MAO-B possess 70 sequence identity. Substrates Biogenic amines 5-Hydroxytryptamine (5-HT) (also known as serotonin) and norepinephrine...

In Silico ADME Tools

The breath and predictive power of in silico ADME tools has increased rapidly during the last 10 years. The quality of many models is such that they can successfully influence decision making in drug discovery and development. In drug discovery they can influence decision related to synthesis of compounds and in development they can influence decisions to perform certain clinical trials or the design of the trial. 10.1 Abbreviations 10.2 Basic Concepts 10.3 Structure-Based Models 10.4...

Advances in Bioanalysis as It Relates to ADME

Bioanalysis continues to play a crucial role in ADME sciences. Most in vitro or in vivo studies have either a quantitative or qualitative bioanalytical endpoint. This chapter provides a general overview of the use of mass spectrometry in ADME sciences and the advantages and disadvantages of the various types of instruments. 8.1 Abbreviations 8.2 Basic Concepts 8.3 Sample 8.4 Sample Extraction 8.5 Chromatographic Separation 8.6 Bioanalysis by LC-MS Absorption, distribution, metabolism, and...

Basic Concepts And Definitions

Metabolism is the main elimination pathway of xenobiotics from the body (see Table 2.1). In equation form, the total in vivo clearance (CL) is represented CLtotal CLrenal + CLbiliary + CLmetabolism + CLothers (2.1) CLrenal and CLbiliary unchanged drug being cleared from urine and bile, respectively. CLmetaboiism the contribution of metabolism, which includes both hepatic and extrahepatic metabolism. CLother any unaccounted for CL Note that CL terms are additive. R. Tecwyn Williams first...

Pharmacokinetics Quick Guide

Drug Metabolism and Pharmacokinetics Quick Guide Drug Metabolism and Pharmacokinetics Quick Guide Siamak Cyrus Khojasteh khojasteh.cyrus gene.com Cornelis E.C.A. Hop hop.cornelis gene.com ISBN 978-1-4419-5628-6 e-ISBN 978-1-4419-5629-3 Springer New York Dordrecht Heidelberg London Library of Congress Control Number 2011923538 Springer Science Business Media, LLC 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the...

Substrates And Inhibitors

Substrates and inhibitors of transporters are, in general, less selective than substrates and inhibitors of P450 enzymes. Tables 4.3 and 4.4 summarize known substrates and inhibitors of select ABC and SLC transporters. Table 4.3. Select ABC transporter substrates and inhibitors Transporter Table 4.3. Select ABC transporter substrates and inhibitors Transporter Table 4.4. Select SLC transporter substrates and inhibitors Table 4.4. Select SLC transporter substrates and inhibitors sulfate,...

Permeability and Efflux Ratio

Permeability is determined commonly using cell culture based models utilizing Caco-2 cells a continuous line of heterogeneous human epithelial colorectal adenocarcinoma cells or MDCK cells Madin-Darby Canine Kidney Cells . In studies where the contribution of specific transporters is examined, MDCK cells over expressing a particular transporter of interest are often utilized. Examples of such MDCK cell lines include MDR1-MDCK P-gp over expressing cells and MRP2-MDCKII cells MRP2 over expressing...

Prediction of Human Pharmacokinetics

The prediction of human pharmacokinetics is an extremely difficult endeavor during the selection of drug candidates for further human clinical testing. Despite a variety of available in vitro and in vivo methodologies, successful predictions are still difficult when performing them prospectively. This chapter gives a general overview of in vitro and in vivo methodologies used to predict human pharmacokinetics. 7.1 List of 7.2 Basic Concepts 7.3 Prediction of Human Fraction Absorbed 129 7.4...

ABC and SLC Transporters

ATP-binding cassette ABC transporters and solute carrier SLC transporters are the two main classes that drug transporters can be categorized into. The ABC family of transporters requires ATP hydrolysis to transport substrates across membranes. Therefore, ABC transporters are primarily active transporters. Notable examples of ABC transporters include P-gp, multidrug resistance-associated protein MRP , and breast cancer resistance protein BCRP . In contrast to ABC transporters, SLC transporters...

Criteria for Determining MBI

Inhibition of DME is time dependent. 2. Inhibition of DME is cofactor dependent e.g., NADPH dependent in the case of P450 enzymes . 3. The presence of another substrate slows down or removes inactivation by competing with the MBI. 4. Inactivation is irreversible and dialysis does not retain its activity. 5. Inactivation takes places with no lag time. 6. Rate of inactivation is first order and saturable. 7. Trapping agents and reactive oxygen species ROS scavengers catalase and superoxide...

Biopharmaceutics Drug Disposition Classification System BDDCS

Recently, Wu and Benet 2005 have proposed classification of drugs that differs from the BCS classification system by using the major route of elimination rather than permeability as the criteria. The categories for BDDCS is as shown below Extensive metabolism Extensive metabolism Poor metabolism Poor metabolism Wu and Benet 2005 propose that it is easier and less ambiguous to determine BDDCS assignments based on the extent of metabolism rather than BCS assignments using permeability i.e.,...

In Vivo Prediction of DDIs for Mechanism Based Inhibitors

Mechanism-based inhibitors inactivate DMEs therefore, the enzyme has to be resynthesized in order to recover to its original activity. In the liver and intestine, there is a constant rate of enzyme synthesis ksyn and enzyme degradation kdeg . In the absence of a mechanism-based inhibitor and at steady-state, ksyn kdeg. In the presence of a mechanism-based inhibitor, the total enzyme degradation rate is increased from its natural rate kdeg by kinact. The net result is a transient decrease in the...

ADME Properties and Their Dependence on Physicochemical Properties

Absorption, distribution, metabolism, and excretion ADME properties such as absorption, clearance, and volume of distribution are strongly influenced by physicochemical parameters. A lot of retrospective analyses have been performed to identify those attributes that give rise to favorable ADME parameters. These attributes should be incorporated in compound design to increase the chance of identifying a compound with superior ADME properties. 9.1 Abbreviations 9.2 Basic Concepts 9.3 Molecular...

Biopharmaceutics Classification System

The BCS classification system is used to categorize drugs and serves to help anticipate whether drugs will have bioavailability bioequivalence problems. BCS classifies drugs according to their solubility and permeability. A drug is considered to have high solubility if drug substance at the highest dose strength for an immediate release formulation can be dissolved in lt 250 mL of water over a pH range of 1-7.5. A high permeability drug is one that has either complete intestinal absorption fa...

Maximum Absorbable Dose

The maximum absorbable dose MAD provides a good conceptual tool to help anticipate oral absorption problems in the evaluation of drug candidates. It is calculated as follows MAD ka X S X Vintestine X T 3.6 where ka is the absorption rate constant in units of time-1 i.e., min-1 or h-1 , S is the solubility of the drug in relevant media in units of concentration i.e., mg mL , Vintestine is the volume of water in the small intestine in units of volume i.e., mL , T is the small intestine transit...

Uridine Diphosphate Glucuronosyltransferases UGTs EC 24117

Subcellular location Luminal side of the ER. Organ distribution Liver, kidney, and intestine, Cofactor Uridine diphosphoglucuronic acid UDPGA , Overall reaction See Fig. 2.6. Figure 2.6. a Mechanism of formation of glucuronide conjugate. X is a nucleophilic site on the molecule such as an oxygen atom in the case of alcohols, phenols and carboxylic acids , a nitrogen atom in the case of amines, azaheterocyclic molecules , or a carbon atom not common, but seen with activated carbons such as...

B

Concentration- and time-dependent inactivation. a natural log of percentage of activity remaining versus time. b the corresponding Figure 5.2. Concentration- and time-dependent inactivation. a natural log of percentage of activity remaining versus time. b the corresponding An IC50 shift assay. Determination of kinact and KI is not suitable for discovery-stage screening purposes, since it is resource intensive and time consuming. In IC50, shift methodology is proposed where different...