11 Simulating of in vivo metabolism taking into account detoxification logics.

Slides:



Advertisements
Similar presentations
SITES DRUG BIOTRANSFORMATION
Advertisements

HLTH 340 Lecture A4 Toxicokinetic processes: Distribution (part-1)
Dosimetry in Risk Assessment and a bit More Mel Andersen McKim Conference QSAR and Aquatic Toxicology & Risk Assessment June 27-29, 2006.
Biotransformation Xenobiotic metabolism
PHASE II: Conjugation Reaction R O S E L Y N A. N A R A N J O.
Drug metabolism Refers to enzyme-mediated biotransformations (detoxication) that alter the pharmacological activity of both endogenous and exogenous compounds.
All biological organisms have defense mechanisms to protect them from the negative effects of small quantities of foreign compounds. These foreign compounds.
DISTRIBUTION The body is a container in which a drug is distributed by blood (different flow to different organs) - but the body is not homogeneous. Factors.
3. Metabolism Many xenobiotics undergo chemical transformation (biotransformation; metabolism) when introduced into biologic systems like the human body.
Activation/Detoxication. Non-polar (lipophilic) Hydrophobic Lipophobic Hydrophilic (Polar) XENOBIOTIC INTERMEDIATE METABOLITE ELIMINATION WATER-SOLUBLE.
Pyridoxal Phosphate (PLP) is a Cofactor for Many Enymes Histidine decarboxylase Pyridoxal phosphate (PLP) PLP Histidine Histamine Binding to H 1 receptors:
1.) fate of xenobiotic -- central role of metabolism Uptake/Transport > Metabolism > Excretion Or Storage 2.) xenobiotic converted.
“What the body does to the drug”
Investigation of Oxidative and Conjugative Metabolism Reactions with Liquid Chromatography / Accurate Mass High Resolution Mass Spectrometry Maciej Bromirski.
Phase-II Drug Metabolism
 The human body has four main excretory pathways that remove environmental toxins (exogenous toxins), as well as toxic prod­ucts produced by the body.
Drug Detoxification Dr. Howaida Supervised by : Prepared by:
Metabolism of Xenobiotics
Advanced Medicinal Chemistry
Biotransformation Xenobiotic metabolism “Essentials of Toxicology” by Klaassen Curtis D. and Watkins John B Chapter 6.
METABOLISM. WHAT IS METABOLISM? OUR BODIES GET THE ENERGY THEY NEED FROM FOOD THROUGH METABOLISM THE CHEMICAL REACTIONS IN THE BODY'S CELLS THAT CONVERT.
28/05/12 Questions (Rispondete alle domande che seguono usando il colore rosso per il testo) Tossicologia - Rubbiani Maristella.
Mechanisms of Toxicity
Biochemical functions of liver
SULFONAMIDES Chapter 19.
Physiologically Based Models of the Lung S. Moll H. Meyer S. Mielordt Seminar Pharmakokinetik - Mathematische Modelle und ihre Anwendung - WS 03/04 FU.
NADPH- Cyt. P450 reductase P450 S SOH O 2 H 2 O e NADPH NADP +
Environmental Biology for Engineers and Scientists D.A. Vaccari, P.F. Strom, and J.E. Alleman © John Wiley & Sons, 2005 Chapter 17 – The Science of Poisons.
Phase II: Conjugation Synthetic reaction of a xenobiotic (or of a Phase I metabolite of a xenobiotic) with an endogenous substance Results in introduction.
Drug Metabolism and Prodrugs
1 Pharmacology Pharmacokinetics –Absorption –Distribution –Biotransformation (metabolism) –Excretion Pharmacodynamics –Receptor binding –Signal transduction.
“Other” detoxication mechanisms P-glycoprotein: ATP-dependent carrier that removes molecules from cells Multidrug resistance associated protein MDR Multispecific.
WP 6 UMR de Toxicologie Alimentaire INRA WP6 : Effects of garlic on carcinogen metabolizing enzymes Milestones :  In vitro effects of garlic compounds.
Phase II: Conjugation Synthetic reaction of a xenobiotic (or of a Phase I metabolite of a xenobiotic) with an endogenous substance Results in introduction.
Terodiline Aromatic p-hydroxylation predominate with R but benzylic hydroxylation is preferred with S (homework)
Chapter 9 Biotransformation
CYP Biotransformations
!!!……Molecular Target Concept A gonist Antagonist.
QSAR in CANCER ASSESSMENT PURPOSE and AGENDA Gilman Veith Duluth MN May 19-21, 2010.
General Mechanisms of Toxin Induced Cell Damage Toxic metabolites can form covalent bonds with target molecules or alter the target molecule by non-covalent.
1 drug molecule Highly lipophyllic lipophilic polar hydrophylic accumulation (fatty tissues) phase I polar phase IIbioinactivation conjugation hydrophylic.
Dr. Muslim Suardi, MSi., Apt.
McKim Conference on Predictive Toxicology The Inn of Lake Superior Duluth, Minnesota September 16-18, 2008 Toxicity Pathways as an Organizing Concept Gilman.
Detoxification Chemicals entering body (mostly via food) must pass through liver.
『창의적 예측경영』『 효율적 내실경영 』 Toxicity Lee, sang-hwi Chapter 17.
Biotransformation of xenobiotics and endogenous toxins in the liver: microsomal oxidation, cytochrome Р-450.
Toxic effects Acute / chronic Reversible / irreversible Immediate / delayed Idiosyncratic - hypersensitivity Local / systemic Target organs.
Pharmacology I BMS 242 Lecture 4 Pharmacokienetic Principles (3&4): Drug Metabolism and Excretion [Elimination] Dr. Aya M. Serry 2016.
Medicinal Chemistry Lecture Drug Metabolism Lectures 11 & 13 Chemical Delivery Systems Joseph O. Oweta | PHS 2201.
Transportation and Transformation of Xenobiotics
Chapter 5 Drug Metabolism
Metabolism - Biotransformation
Metabolism & Detoxification
METABOLISM / BIOTRANSFORMATION of TOXICANTS.
Metabolism of drugs and xenobiotics
METABOLISM OF XENOBIOTICS
Metabolic Changes of Drugs and Related Organic Compounds
Phase-II Drug Metabolism Pharmaceutical Medicinal Chemistry-I
Chapter 08 Drug Metabolism.
Phase-I Drug Metabolism Pharmaceutical Medicinal Chemistry-I
Drug conjugation pathways (phase II)
Biological targets and phase II metabolism of chemopreventive licorice compounds. Biological targets and phase II metabolism of chemopreventive licorice.
Xenobiotic or Drug Metabolism
Part II Ovanes Mekenyan, Milen Todorov, Ksenia Gerova
Ovanes Mekenyan, Milen Todorov, Ksenia Gerova
Drug Detoxification Dr. Howaida Supervised by : Prepared by:
Metabolism of drugs and xenobiotics
The Category Approach for Predicting Mutagenicity and Carcinogenicity
Pharmacokinetics/Pharmacodynamics
Disposition of toxic compounds and Its Metabolic reaction
Presentation transcript:

11 Simulating of in vivo metabolism taking into account detoxification logics

12 AMES CA Liver Bone Marrow Blood Transport Activation (Phase I) Conjugation (Phase II) DNA/Protein reactivity no pharmacokinetics factors Activation (Phase I) Conjugation (Phase II) DNA/Protein reactivity pharmacokinetics factors in vivo detoxification “logic” Effect in vivo bio-exhausting in vitro Genotoxicity in vivo Genotoxicity Levels of GT Investigation

13 Levels of GT Investigation: First-Pass Metabolism? in vivo liver genotoxicity in vivo MN genotoxicity negative Level ILevel II Level III in vitro mutagenicity negative positive negative (metabolic detoxification in liver) positive negative (bio-exhausting) positive chemical

14 Levels of GT Investigation: First-Pass Metabolism? in vivo liver genotoxicity in vivo MN genotoxicity negative Level ILevel II Level III in vitro mutagenicity negative positive negative (metabolic detoxification in liver) positive negative (bio-exhausting) positive

15 Levels of GT Investigation: First-Pass Metabolism? in vivo liver genotoxicity in vivo MN genotoxicity negative Level ILevel II Level III in vitro mutagenicity negative positive negative (metabolic detoxification in liver) positive negative (bio-exhausting) positive

16 Simulating of in vivo metabolism taking into account detoxification and bio-exhausting

17 Simulating of in vivo detoxification  simulating in vivo detoxification  simulating in vivo bio-exhausting

18 Simulating of in vivo detoxification  simulating in vivo detoxification  simulating in vivo bio-exhausting

19 In vivo Detoxification Includes:  Principal phase II metabolic detoxification reactions:  glutathione conjugation  glucuronidation  amino acid conjugation  acetylation  sulfation  Detoxification “logic” (Complete metabolic detoxification suppresses genotoxic action of reactive intermediates in liver).

110 In vivo Detoxification of Styrene (in vivo metabolism)

111 R=Aryl DNA reactivity observed in vitro Protein binding observed in vitro In vitro genotoxic effects of styrene epoxide Styrene oxide is hydrolyzed in vitro to styrene glycol by microsomal epoxide hydrolase from the liver, kidneys, intestine, lungs, and skin of several mammalian species (Oesch 1973, cited in IARC 1985). Observed in vitro metabolic pathway for styrene

112 Mutagenic effects of styrene in vivo can be expected under extreme exposure conditions if styrene oxide is not efficiently detoxified and primary DNA lesions are not completely repaired. (Speit et al. 2008). R=Aryl DNA reactivity observed in vitro Protein binding observed in vitro “Trapped” metabolite due to the “channeling” effect Observed in vivo MNT metabolic pathway for styrene

113 Observed in vivo MNT metabolic pathway for styrene A recent published data for in vivo MNT in bone marrow cells of mice was clearly negative (Speit et al. 2008). R=Aryl DNA reactivity observed in vitro Protein binding observed in vitro “Trapped” metabolite due to the “channeling” effect

114 Simulating in vivo detoxification of styrene by TIMES

115

116 “Trapped” reactive metabolites in in vivo detoxification Pathway I

117 “Trapped” reactive metabolites in in vivo detoxification Pathway II

118 Implementation of Detoxification “Logic” Related to In Vivo Bone Marrow MNT Test Results – Classes of Chemicals Studied  Aromatic amines  Organic halides  Nitro compounds  Epoxides  Ureides  Isocyanates

119  Aromatic amines  Organic halides  Nitro compounds  Epoxides  Ureides  Isocyanates Example: Preventing in vivo N-Hydroxylation Y = –SO 3 H, -COOH, COOR, -P(=O)(OH) 2, phosphate, thiopohosphate, etc. Observation: Polar functional groups in aromatic amines prevent phase I N-hydroxylation as bioactivation reaction. Reasoning:  the chemicals are already polar enough to be subjected to phase II detoxification reaction;  electron-withdrawing functional groups hamper the aromatic amine N-hydroxylation Implementation of Detoxification “Logic” Related to In Vivo Bone Marrow MNT Test Results – Classes of Chemicals Studied

120 Simulating of in vivo detoxification  simulating in vivo detoxification  simulating in vivo bio-exhausting

121 The in vivo bio-exhausting detoxification scenarios include: highly reactive metabolites of liver GT chemicals are bio-exhausted approaching to the MN bone marrow due to off-target reactions, therefore, they become incapable of producing harmful effects on the target tissue (bone marrow). bio-exhausting of short – lived intermediates formed in liver Bio-exhausting Detoxification Scenarios:

122 Negative in vivo GT (MNT) effect of Nitrobenzene

123 Negative in vivo GT (MNT) effect of Nitrobenzene “Trapped” reactive metabolites in in vivo detoxification Pathway I Liver genotoxic metabolite is further bio-exhausted along its path to the bone marrow

124 Negative in vivo GT (MNT) effect of Nitrobenzene “Trapped” reactive metabolites in in vivo detoxification Pathway II Liver genotoxic metabolite is further bio-exhausted along its path to the bone marrow

125 Negative in vivo GT (MNT) effect of Nitrobenzene “Trapped” reactive metabolites in in vivo detoxification Pathway III Liver genotoxic metabolite is further bio-exhausted along its path to the bone marrow