James Med chem Mod 4

Phase two metabolites are usually what at phys pH?

 

ANIONS
These Phase II metabolites are not an ANION at physiological pH

Methylated

 

Fatty  acid

 

&

 

Acetylated metabolites

Acetaminophen metabolized by which CYPS?

CYP1A2

 

CYP2E1

 

CYP3A4

 

 

CYP2D6 ASSOCIATED WITH WHAT OLD DRUG ANTI htn MED?

DEBRISOQUINE

 

[NO ACTIVE CYP2D6 MADE PEOPLES BP LOWER WAY TOO MUCH]

CODEINE IS A PRODRUG. THE ALTERED FUNCTION OF _____________ CAUSES CODEINE NOT TO WRK IN SOME PEOPLE
CYP2D6

CYP2C19 FIRST SHOWN WITH WHAT DRUG_____

 

AFFECTS WHAT POP?_____

MEPHENYTOIN

 

 

asian/japanese (20-30%)

 

 

NEWBORNS HAVE LOW LEVELS OF _________

ugt

 

[HARD FOR BABIES TO EXCRETE/METAABOLIZE BILLIRUBIN SO THEY DEVELOP JAUNDICE]

SlOW ACETYLATORS (can cause toxicity)

 

ASIANS 

 

SWEDISH

 

GENERAL US

ASIANS [0-30%]

 

SWEDISH [70%]

 

GENERAL US [50%]

isoniazid treats___________

 

isoniazid uses wat enzyme to become inactive?___

TUBERCULOSIS

 

 

NAT-2[N-acetyltransferase 2] (CAN USE CYP2E1 TOO)

SOME PEOPLE EXPRESS UNSTABLE CYP2D6 THEY ARE ___________

 

soME HAV EXTRA COPIES

_____________

SLOW-noN 

 

ULTRA-RAPID METABOLIZERS (hIGH IN ARAB/AFRICAN)

WHICH CYPS ARE INDUCED BY 

 

TOBACCO,CHARCOAL

 

ETHANOL

 

ST. JOHNS WORT

TOBACCO,CHARCOAL [CYP1A2]

 

ETHANOL [CYP2E1]

 

ST. JOHNS WORT [CYP3A4]

rIFAMPIN CONTRAINDICATED WITH OCs WHY?

CYP3A4 INDUCED BY RIFAMPIN

 

OCs METABOLIZED TO FAST AND YOU GET UNPLANNED PREGNANCY

tHEOPHYLLINE CONTRAINDICATED WITH CHARCOAL BROILED FOODS WHY?

BOTH USE CYP1A2

 

[MAKES THEOPHYLLINE NO LONGER EFFECTIVE]

 

EETHANOL REDUCES ______ AND ______ CONCENTRATION LEADING TO POOR ___&&___

nadph & udpga

 

 

 

monooxygenation & glucuronidation

AIDS  medication use __________ to bind ritonavir and avoid first pass of indinavir and saquinavir
CYP3A4
KETOCONAZOLE AND CIMETIDINE INHIBIT SEVERAL FORM S OF CYP BY _______________
BINDING /OCCUPYING HEMOGOLOBIN BINDING SITE OF CYP
ERYTHROMYCIN INHIBITS _______BY BINDING TIGHTLY AND PREVENTING METABOLISM OF OTHER RX
CYP3A4
THE LONE PAIR ON __________CONTAINING DRUGS OCCUPY O2 BINDING SITE ON CYP450 & PREVENT OXYGENATION OF OTHER DRUGS

IMIDAZOLE

[image]

GRAPEFRUIT INTERXN OCCUR WHERE

 

W/ WHAT ENZYMES

Enterocytes

 

CYP3A4 &

OR W/ DRUGS THAT ARE SUBSTRATE FOR P-GLYCOPROTEIN [MDR1]

HYDROPHILLIC METABOLITES ARE USUALLY
INACTIVE

EXAMPLE OF :

 

ACTIVE RX>ACTIVE METABOLITE

 

ACTIVE RX > INACTIVE METABOLITE

 

iNACTIVE RX > ACTIVE METABOLITE

ACT RX>ACT [DIAZEPAM TO N-DESMEHTL,…]

 

ACT RX > INACT [ISONIAIZD TO N ACETYL,….]

 

iNACT RX > ACT [IRINOTECAN TO 2N-38]

Phase I

Hydrolysis

 

Oxydation

 

Reduction

Phase II

Amino acid Conjugation

 

Glutathione Conjugation

 

Glucuronidation

 

Acetylation

 

Sulfonation

Other Phase II

Fatty acid conjugation

 

Methylation

 

Cholesterol Conjugation

Hydrolysis

-Phase I (H2O catalyse)

 

-Peptidase

 

-Epoxide

 

-Amide Hydrolyses

 

-Ester hydrolyses

Oxidation

-Phase I []

-Flavin monooxygenase[NADPH, O2]

-Alcohol & Aldehyde Dehydrogenase[NADPH,NADH,O2]

-Monoamine Oxidase[NADH,O2]

-CYP[NADPH,O2]

 

CYP450 oxidation

phase I [*DAAD NONE*]

 

-Desaturation

-Aromatic ring hydroxylation

-Aliphatic hydroxylation

-Dehalogenation

 

-N & S Oxidation

-O Dealkylation

-N Dealkylation

-Epoxidation

Reduction

-Phase I

 

(NADPH)

 

-Nitrogrp to amino grp[nitroreductase enzyme]

-Azo group to amino grp

Acetylation

PHASE II

 

Catalyzed: NAT

 

Co-Substrate: ACETYL-COA

 

NOT ANIONIC METABOLITES

GLUCURONIDES

PHASE II

 

Catalyzed: UGT

 

Co-Substrate: UDPGA

 

GROUPS-(*ATACH*)—-Amine,Thiol,Acidic carbons,Carboxylic acids,Hydroxyl

GLUTATHIONE

PHASE II

 

Catalyzed: GST

 

Co-Substrate: GSH(glutathione)

 

GROUPS—-alkyl halides,aryl halides,alpha-beta unsat ketones,epoxides

 

DETOXIFYING AGENT

AMINO ACID CONJUGATION(Hippuric acid)

PHASE II

 

Catalyzed: ACYL COA LIGASE, then ACYL COA N-ACETYLTRANSFERASE

 

Co-Substrate: GLYCINE, SOMETIMES GLUTAMINE OR TAURINE

 

GROUPS—-carb acids

Sulfonation

 

PHASE II

 

Catalyzed:SULT

 

Co-Substrate:PAPS

 

GROUPS—hydroxyls, amines

FATTY ACID CONJUGATION

OTHER PHASE II

 

Catalyzed: AMIDASE OR ESTERASE

 

 

METHYLATION

OTHER PHASE II

 

Catalyzed: S-ADENOSINE METHYL TRANSFERASE

 

Co-Substrate: SAM

CHOLESTEROL CONJUGATION

OTHER PHASE II

 

CATALYSE: HYDROLASE

REACTIVITY [least to most reactive func. grps]

CAEKA

 

carb acid, amide, ester, ketone,aldehyde

UGT1A1

 

substrate:_____

 

gene deletion:______

 

reduced expression:_______

 

substrate: billirubin

 

gene deletion: Crigler-Nager syndrome

(severe unconjugated bilirubemia)

 

reduced expression: Gilberts Syndrome

[1.common variant UGT1A1*28]

[2.IRINOTECAN Tx for Colon Cancer]

THESE PHASE II METABOLITESARE NOT WATER SOLUBLE

[*FMC*]

 

FATTY ACID CONJUGATION, CHOLESTEROL CONJUGATION, METHYLATION

THESE METABOLITES INCLUDE PROTEIN AIDED REMOVAL OF DRUGS FROM THE CELL

[termed by scientists]

PHASE III METABOLITES
CYP CYCLE
[image]
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