By Ala F. Nassar

ISBN-10: 0470504781

ISBN-13: 9780470504789

ISBN-10: 047089038X

ISBN-13: 9780470890387

The target of this publication is to enhance the readers' wisdom of metabolite elucidation in drug metabolism by way of exposing them to extensive insurance of the biotransformation of xenobiotics, recommendations for picking out and characterizing metabolites, FDA instructions, and case reviews on tips on how to increase the decision-making method in structural amendment of drug applicants to minimize toxicity.

The publication contains eight chapters; it first offers an advent on biotransformation of xenobiotics, after which offers glossy methods and methods for facing metabolite characterization, utilizing instruments comparable to LC-MS, H-D alternate, sturdy isotopes LC-MS-NMR, and radiolabeled compounds. additionally, concepts for facing reactive intermediates in drug discovery and improvement are provided in addition to case reviews on bettering the decision-making technique within the structural amendment of drug applicants. The final bankruptcy discusses the regulatory views of protection checking out of drug metabolites and why, how, and whilst to check their safety.Content:
Chapter 1 Human Biotransformation (pages 1–77): Andrew Parkinson, Brian W. Ogilvie, Brandy L. Paris, Tiffini N. Hensley and Greg J. Loewen
Chapter 2 Analytical instruments and techniques for Metabolite identity in Drug Metabolism (pages 79–123): Yongmei Li
Chapter three instruments of selection for Accelerating Metabolite identity: Mass Spectrometry expertise Drives Metabolite identity reviews ahead (pages 125–162): Ala F. Nassar
Chapter four enhancing Drug layout: issues for the Structural amendment approach (pages 163–216): Ala F. Nassar
Chapter five Case examine: The Unanticipated lack of N2 from Novel DNA Alkylating Agent Laromustine by way of Collision?Induced Dissociation: Novel Rearrangements (pages 217–228): Ala F. Nassar, Jing Du, David Roberts, Kevin Lin, Mike Belcourt, Ivan King and Tukiet T. Lam
Chapter 6 Case research: identity of in vitro Metabolite/Decomposition items of the unconventional DNA Alkylating Agent Laromustine (pages 229–244): Ala F. Nassar, Jing Du, David Roberts, Kevin Lin, Mike Belcourt, Ivan King and Tukiet T. Lam
Chapter 7 ideas for the Detection of Reactive Intermediates in Drug Discovery and improvement (pages 245–294): Mark P. Grillo
Chapter eight defense checking out of Drug Metabolites: Mist information effect at the perform of commercial Drug Metabolism (pages 295–312): J. Greg Slatter

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Extra resources for Biotransformation and Metabolite Elucidation of Xenobiotics

Example text

Four in vitro approaches have been developed for reaction phenotyping. , 2008). The four approaches to reaction phenotyping are: 1. indd 37 8/19/2010 5:31:52 PM 38 HUMAN BIOTRANSFORMATION CYP enzymes in the same microsomal samples. This approach is successful because the levels of the CYP enzymes in human liver microsomes vary enormously from sample to sample (up to 100-fold) but, with judicious sample selection, they can vary independently from each other. 2. 5, on the metabolism of a drug by human liver microsomes.

B Km and Vmax were determined with a pool of 50. c Testosterone 6β-hydroxylation by CYP3A4/5 shows positive (homotropic) cooperativity. 3. indd 36 8/19/2010 5:31:52 PM c,d Fluoxetine Methadone Mibefradil Paroxetinec,d Quinidinea,c Sertralinef Terbinafinee CYP2D6 Amiodarone Buproprion Chlorpheniramine Cimetidine Clomipramine Duloxetinee Haloperidol NA f (CONTINED) Amprenavir Avasimibe Bosentan Carbamazepinec Clotrimazole Cyproterone acetate Dexamethasoneb Amiodarone Amprenavire Aprepitante Atazanavirc,d Azamulinb Bosentan Fluvoxamine Fosamprenavire Gestodene Grapefruit Juice Ketoconazolea,c,d Indinavirc,d Nifedipine Omeprazole Paclitaxelb PCBs Phenobarbitalb Phenytoinb Rifabutin Efavirenz Etoposide Guggulsterone Hyperforin Lovastatin Mifepristone Nelfinavir CYP3A4 Cimetidine Clarithromycinc,d Diltiazeme Erythromycine Felbamate Fluconazolee f Saquinavirc,d St.

Indd 46 8/19/2010 5:31:53 PM DRUG METABOLISM FROM AN ENZYME PERSPECTIVE 47 tude of the interaction is less than that observed for CYP induction. , 2006). In spite of the limited number of reports of UGTmediated DDIs, UGT enzymes are increasingly involved in the metabolism of new drug candidates. The apparent increased involvement of UGT enzymes is due in part to the selection process for new drug candidates, which is often biased against chemicals that interact with CYP enzymes. The selection of chemicals with little potential of inhibiting CYP enzymes, chemicals that are metabolically stable in NADPH-fortified human liver microsomes, and chemicals with high aqueous solubility are chemicals that are more likely to be metabolized by UGT than CYP.

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Biotransformation and Metabolite Elucidation of Xenobiotics by Ala F. Nassar


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