Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Slide 38Slide 39Slide 40Slide 41Slide 42Slide 43Slide 44Slide 45Chemistry 377 - Drugs and Poisons1METABOLISM (biotransformaton)METABOLISM (biotransformaton)PurposeTo convert lipophilic substances into hydrophilic species for subsequent excretion.MetabolismA D EWhere does it occur?D&P Fall 11Chemistry 377 - Drugs and Poisons2MetabolismLiver substructuresD&P Fall 11Chemistry 377 - Drugs and Poisons3SERsmoothendoplasmicreticulumTwo major sets of enzymatic pathwaysPhase 1 - nonsynthetic reactions Phase 2 - synthetic reactionsMetabolismLivermicrosomesHow does it occur?D&P Fall 11Chemistry 377 - Drugs and Poisons4oxidationreductionhydrolysis•hydroxylationsaromatic, aliphatic, nitrogen•dealkylations(N-, S-, P)•deaminations•N-, S-, P- oxidations•S-replacements•epoxidations•others•azo reduction•nitro reduction•disulfide reduction•othersNonsynthetic Reactionsoxidoreductasesoxidases monoamine oxidases mixed function oxidasesoxidoreductasesreductases•esters•amides•hemiacetals,acetals, hemiketals, ketalsesterasesamidasespeptidaseslipaseshydrolasesMetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons5A principal reaction of drug/toxin metabolism is OXIDATION.The enzymes responsible are oxido-reductases; called mixed-functionoxidases.Most prominent andimportant among theseis thecytochrome P450system.consists ofCyt P 450 andCyt P 450 reductase andother cofactors1-3 proteins depending on organism and sitecytochrome P 450Fe3+protoporphryrinring systemBIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONMetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons6EnzymesTransferasesHydrolasesOxido-ReductasesIsomerasesLyasesLIgasesOxidasesOxygenasesDehydrogenasesReductasesMonoxygenasesDioxygenasesInternalMonoxygenasesExternalMonoxygenasesCYTOCHROMES P450E.C.C.MetabolismE.C. 1 oxido-reductasesE.C. 2 transferasesE.C. 3 hydrolasesE.C. 4 lyasesE.C. 5 isomerasesE.C. 6 ligasesCYP E.C. 1.6.2.4NADPH-hemoprotein reductaseactually a heme-thiolateD&P Fall 11Chemistry 377 - Drugs and Poisons7BIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONMetabolismsome types of CYP assembliesD&P Fall 11Chemistry 377 - Drugs and Poisons8OHCYP450Fe3+CYP450Fe3+CYP450Fe2+2+CYP450Fe2+CYP450Fe2+CYP450Fe3+CYP450Fe3+DRUGDRUGDRUGDRUGDRUGDRUGDRUGDRUGCYP450reductaseNADPH + H+e-O2O2e-O21- H2O..:Figure 2.4 –CYP450 Reaction SequenceONADPH + H+OH H+DRUGBIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONMetabolismunstable Fe—O2 complexD&P Fall 11Chemistry 377 - Drugs and Poisons9NNOOOHHCH2CH2CHCH2CH3NNOO OHHCH2CH3NNOO OHHCH2CH3CH(CH3)CH2CH2CH3CH3CH3NNOO OHHCH2CH2C(CH3)2CH2CH3OHNNOO OHHCH2CH3OHNNOO OHHCH2CH3CH(CH3)CH2CHCH3OHThe following three reactions involve the central nervous system depressants known as barbiturates.PentobarbitalPhenobarbitalAmobarbitalhydroxylationshydroxylationsaliphaticaromaticaliphaticBIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONRH + NADPH + H+ + O2 ROH + NADP+ + H2O MetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons10NNClCH3ONNClHOOCH HWhich is the oxidized andwhich is the reducedproduct?+Diazepam(Valium®)dealkylationCH2CHNH2CH3CH2CCH3O+ NH3AmphetaminedeaminationNH2NO2OCNHCH3H3CCH3SCH3OOCNHCH3H3CCH3SCH3OOAnilineNitrobenzeneMethiocarb(an insecticide)a sulfoxideN-, S-, P- oxidationThis type of reaction is also catalyzed by deaminases and transaminases. For example, it is a way for amino acids to beincorporated into the Krebs cycle.However, the mechanism is entirelydifferent.Probably catalyzed via aperoxygenase mechanism.BIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONMetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons11SPC H3C H2OO C H2C H3OO PC H3C H2OO C H2C H3OParathionParaoxonS-replacementCCl2CH2ClClClClCCl2CH2ClClClClOAldrin DieldrinBoth compounds areinsecticides.epoxidationBIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONMetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons12Distribution of CYP450 in HumansCYP 1A2CYP 2A6CYP 2B6CYP 2C19CYP 2C9CYP 2D6CYP 2E1CYP 3A43A42D61A22C192C9BIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONMetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons13http://www.fda.gov/cder/drug/drugReactions/CERT%20Educational%20Module%201/sld038.htmBIOTRANSFORMATION - NONSYNTHETIC - OXIDATION4/5MetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons14rate of biotransformationPMEMUEMpercent of populationphenotype - variants expressed in >2% of the populationPM - poor metabolizersEM - extensive metabolizersUEM - ultra extensive metabolizersPharmacogenomicsBIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONphenotype-genetic and environmentalgenotype-genetic variationspolymorphism-individual variationsMetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons15The CYP3A family is responsiblefor 30% of the cytochromes inthe liver and 70% in the gut.Metabolizes more medications and hormones than any other CYP.subfamiliesCYP3A3CYP3A4CYP3A5etc.97% identical in aa sequencestomachBIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONliver and small intestineMetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons16systemic antifungalsmacrolide antibioticsBIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONcomponent believed responsible belongs to the furanocoumarinfamily (also known as psoralens).MetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons17BIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONMetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons18http://medicine.iupui.edu/flockhart/clinlist.htmlalso caffeineBIOTRANSFORMATION - NONSYNTHETIC - OXIDATIONInduction - increase in activity caused by a xenobioticMetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons19NNOOCH3(CH2)3phenylbutazoneN NOO OH HC2H5C6H5phenobarbitalCYP450CYP450 3A4,5,7, 2B6actually affects a transport protein (P-gp, MDR1)benzo(a)pyreneCYP450 1A2St. John’s wort CYP450 3A4,5,7actually affects a transport protein (P-gp, MDR1)CYP450 2E1 CH3CH2OHMetabolismD&P Fall 11Chemistry 377 - Drugs and Poisons20Table 3.1 – CYP450 Substrates, Inhibitors, and Inducers*CYPSubstratesInhibitorsInducersCYP1A2caffeineciprofloxacincigarette