Drug Metabolism Overview

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Drug Metabolism Overview. Dr. Arthur Roberts. Where to Find Information. eLC www.pharmwiki.org most up to date correct errors. Outline. Introduction ADME Functions Phase I versus Phase II Metabolism Enzymes Localization Regulation Phase I Metabolism Types of Reactions - PowerPoint PPT Presentation

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Drug Metabolism

Drug Metabolism OverviewDr. Arthur Roberts1Where to Find InformationeLCwww.pharmwiki.orgmost up to datecorrect errors2OutlineIntroductionADMEFunctionsPhase I versus Phase II MetabolismEnzymesLocalizationRegulationPhase I MetabolismTypes of ReactionsFirst Pass EffectPhase II Drug MetabolismTypes of ReactionsFactors that Influence Drug MetabolismConsiderations and Methods

3MetabolitesDrug MetabolismExcretionNon-enzymatic

DistributionAbsorptionBloodDrug4FunctionsGood Drug ClearanceToxin Removal*Homeostasis and Regulation*Prodrug (inactive) Active Drug*BadReduced EfficacyIncreased Toxicity*5Functions: Toxin Removal

bisphenol ASulfonationGlucuronidation

6http://www.sciencedirect.com/science/article/pii/S0041008X070056136Functions: Homeostasis and Regulation

7http://www.ncbi.nlm.nih.gov/pubmed/21395541http://www.sciencedirect.com/science/article/pii/S0169409X990000837Functions: Prodrug Drug

AntidepressantAntihistamine(Fura et al., 2004)AntihistamineAnalgesic81.Zhang, D., Zhu, M., and Humphreys, W. G. (2008) Drug metabolism in drug design and development : basic concepts and practice, Wiley-Interscience, Hoboken, N.J.

8What is the purpose of a prodrug?9Improve ADME and Bioavailability9Functions: Increased Toxicity

Toxic Pathway10Pathways of Drug MetabolismOxidation and ReductionConjugation

Drugs

11Phase I versus Phase II?

12ABCDWhy is it called Phase I and Phase II drug metabolism?13

Evans, W. E., and Relling, M. V. (1999) Pharmacogenomics: translating functional genomics into rational therapeutics, Science 286, 487-491.

14ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; CYP, cytochrome P450; DPD, dihydropyrimidine dehydrogenase; NQO1, NADPH: quinone oxidoreductase or DT diaphorase; COMT, catechol O-methyltransferase; GST, glutathione S-transferase; HMT, histamine methyltransferase; NAT, N-acetyltransferase; STs, sulfotransferases; TPMT, thiopurine methyltransferase; UGTs, urdine 5-triphosphate glucuronosyltransferases.14Localization: Tissue

LiverIntestines

Kidneys15Localization: SubcellularPhase ICytochrome P450s (P450s or CYPs)-ER lumenFlavin-Containing Monooxygenase (FMO)-ER lumenAlcohol Dehydrogenase (ADH)-CytosolPhase IIUDP-glucuronosyltransferases (UGTs)- ER lumenMembrane-bound Sulfotransferases (SULTs)- Golgi ApparatusCytosolic Glutathione-S-Transferases (GSTs)- Cytosol

16http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/16What is the purpose of a drug-metabolizing enzyme being membrane bound?17RegulationInductionActivationInhibition18Regulation: Induction

(Xie, 2004)19http://www.sciencedirect.com/science/article/pii/S1359644604030612Abbreviations: PXR, pregnane X receptor; CAR, constitutive androstane receptor; FXR, farnesoid X receptor; VDR, vitamin D receptor; HNF4, hepatic nuclear factor 4; CYPs, cytochrome P450 family; UGT, UDP-glucuronosyltransferases; SULT, sulfotransferase; GST, glutathione S-transferases; MRP2, multidrug resistance-associated protein 2; MDR1, multidrug resistance protein 1; OATP2, organic anion transporter polypeptide 2.

19Regulation: Induction

(Xie, 2004)DNA20http://www.sciencedirect.com/science/article/pii/S1359644604030612Constitutive androstane receptor, CAR; pregnane X receptor, PXR; retinoid X receptor, RXR; XRE, xenobiotics response elements20Regulation: ActivationDrug ConcentrationRate of Metabolite formation

Testosterone21Ask why it is problematic for In Vivo.21Regulation: InhibitionRate of Metabolite FormationInhibitor Concentration

Bergamottin

22What is an absolute requirement for inhibitor to work In-Vivo? (Reversible, High Affinity), No suicide inhibitors22Phase I First Pass Metabolism

23eCompound.com23Cytochrome P450Hydroxylations

Dealkylations

24http://users.humboldt.edu/rpaselk/C451.S10/C451LecNotes/451nLec12.html24Non-cytochrome P450sAlcohol Dehydrogenase

Epoxide Hydroxylase25http://pubs.rsc.org/en/content/articlelanding/2010/np/b809416k25First Pass Effectconcentration of a drug is greatly reduced before it reaches the systemic circulation.

Morphine

Demerol

Lidocaine(opioid analgesic)(synthetic opioid analgesic)(local anesthetic)26Morphine=Opiate analgesic;Demerol=Opiate Analgesic; Lidocaine=Local Anesthetic26First Pass EffectConcentration in BloodTimeOralIVWhich corresponds to first pass effect?27Ask them which one corresponds to the first pass effect?27Systems Involved

LiverStomach (Gut Wall)GastrointestinalBacteria28Phase II Reactions

29http://users.humboldt.edu/rpaselk/C451.S10/C451LecNotes/451nLec13.html29Phase II Enzymes

30

Glutathione-S-transferases (GSTs)N-acetyltransferases (NATs)

UDP Glucuronosyltransferases (UGTs)http://users.humboldt.edu/rpaselk/C451.S10/C451LecNotes/451nLec13.html30

ABCD31Factors that Influence Drug Metabolism32Genetics

Poor MetabolizerDifferences in Hydrocodone metabolite formation in Cytochrome P450 2D6Extensive Metabolizer(Reynolds, 2008 Clinics in Laboratory Medicine) 33http://www.sciencedirect.com/science/article/pii/S027227120800043733

web2.uconn.edu/rusling/Carl_Davis1.pptEthnic Groups34Aging(Kinirons, 2003, British Journal of Clinical Pharmacology)

35http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884487/35Gender

[Drug]MaleFemaleCircles=NicardipineTriangles=NifedipineNormalized mRNA Expression Level(Konno, 2004 Toxicology and Applied Pharmacology)36http://www.ncbi.nlm.nih.gov/pubmed/11859684http://molpharm.aspetjournals.org/content/76/2/215.abstracthttp://www.sciencedirect.com/science/article/pii/1357272594000565http://www.sciencedirect.com/science/article/pii/S0041008X0300585436Pregnancy

(Choi, 2011 Biochemical Pharmacology)37http://informahealthcare.com/doi/abs/10.1517/17425251003677755http://www.sciencedirect.com/science/article/pii/S000629521100006237Food, Diet and Nutrition

(Ryu, 2003 Food and Chemical Toxicology)(Kola nut, grape, green tea and Ginkgo biloba)38http://www.sciencedirect.com/science/article/pii/S0278691503000371

38Food, Diet and Nutrition

(Lown, 1997 Journal of Clinical Investigation)waterchronic grapefruit juiceacute grapefruit juice

Felodipine(Calcium Channel Blocker)39http://www.ncbi.nlm.nih.gov/pmc/articles/PMC508096/39ObesityDecreased MetabolismCYP3A4Increased MetabolismUGTs, NAT, XO, CYP2E1, CYP1A2, CYP2C9, CYP2C19, CYP2D6(Brill, 2012 Clinical Pharmacokinetics)40http://www.ncbi.nlm.nih.gov/pubmed/22448619http://www.ncbi.nlm.nih.gov/pubmed/785940740Habits: Alcoholism

ABA- Non-alcoholicB- Chronic alcohol consumption(Lieber, 2008 Biochemical and Biophysical Research Communication)41www.ncbi.nlm.nih.gov/pubmed/785940741Habits: Smoking

(Ryu, 2003 Food and Chemical Toxicology)42http://www.sciencedirect.com/science/article/pii/S027869150300037142Factors that Influence Drug MetabolismGeneticsEthnic GroupsAgeGenderPregnancyFood, Diet and NutritionObesityHabits (Smoking/Alcohol)43Ideas on how to deal with these differences?44End of Overview45