Pharm 5: Drug Metabolism

Front 1

which characteristics of drug metabolites make them more easily excreted from the body

Back 1

more polar, hydrophillic

Front 2

define prodrug

Back 2

drug that is convered into its active state by metabolic enzymes

Front 3

What occurs in phase I metabolism

Back 3

introduction/ revealation of a functional group, oxidation, reduction, dealkylation, hydrolysis

Front 4

what occurs in phase II metabolism

Back 4

conjugation of the drug or drug metabolite to an endogenous substrate molecule

Front 5

describe the organ distrubution of drug metabolising enzymes

Back 5

liver has the most, GI, kidneys and lungs have signifiacnt, all tissues have some

Front 6

What is the subcellular distribution of phase I and II enzymes

Back 6

I=usually in smooth ER, II=cytosolic

Front 7

what are the required components of the P450 reaction

Back 7

cytochrome P450, P450 reductase, NADPH, O2, drug substate

Front 8

What is the net reaction of the P450 system

Back 8

drug+O2+2e-+2H+=> SO + H2O

Front 9

Where is the P450 system localized

Back 9

anchored to the cytoplasmic face of the smooth ER

Front 10

what is the function of P450 reductase

Back 10

a flavoprotein that  provides the 2e- the P450 needs to complete the reaction, Accepts electrons from NADPH

Front 11

The majority of drugs are handled by which 3 CYP's? %?

Back 11

CYP3A-50%, CYP2D6=25%, CYP2C9=15%

Front 12

this CYP handles 50% of drugs

Back 12

CYP3A-50%, CYP2D6=25%, CYP2C9=15%

Front 13

this CYP handles 25% of drugs

Back 13

CYP2D6

Front 14

This CYP handles 15% of drugs

Back 14

CYP2C9

Front 15

What is the funciton of FMO? Rxn?

Back 15

another Phase I enzyme, monooxygenation of soft nucleophiles, drug+O2+2e-+ 2H+=> SO + H2O, very non-selective of substrate, required components are FMO, NADPH, O2, and drug, note that no accessory protein is needed to get e-'s, FMO3 is major isoform, 2-3% of all liver protiens

Front 16

Glucuronidation is an example of a PHase II reaction. Give the HEI, Enzyme, and location

Back 16

UDP-glucuronic acid, UDP glucuronosyl transferase (UGT), ER, high conjugation capacity and abundance of raw materials

Front 17

Acetylation is an example of a phase II rxn. Give the HEI, enzyme, and location

Back 17

acetyl-CoA, N-acetyltranserases (NET), cytosol, variable capacity and raw materials

Front 18

sulfonation is an example of a phase II rxn, Give the HEI, enzyme, and location

Back 18

PAPS, sulfotransferases (SULT) cytosolic, low congujatin capacity and abundance of raw materials

Front 19

Glutathione conjugation is a phase II reaction. Give the HEI, enzyme, and location

Back 19

HEI=drug itself, glutathione S-transferase (GST, cytosol and ER, low conjugation capacity and raw materials

Front 20

give the order of phase II enzymes in terms of % of drugs handled

Back 20

UGT>SULT>NATs>GST
(ugly sluts never get some)

Front 21

which two factors limit the Vmax of phase II enzymes

Back 21

conventional enzyme kinetics and conjugant supply

Front 22

describe enzyme induction

Back 22

exposure to drugs/ chemicals in upregulate enzyme activity/ amount, usually a transcriptional increase so effect takes a while to manifest, can increase or decrease drug effects of several drugs because of broad substrate specificity

Front 23

describe enzyme inhibition in terms of drug metabolism

Back 23

drug or chemical may inhibit the metaboism of several drugs, can be compeititve or non-conpetitive Eg. CYP2D6 metabolizes 25% of drugs but is a small % of CYPs activity can be reduced to near 0, grapefruit juice inhibits CYP3A (50% of drugs), increases F, note FMOs not significantly induced or inhibited

Front 24

Describe acetaminophen metabolism and how EtOH effects this

Back 24

80% phase II by UGT, 15% by SULT, reminder phase by CYP2EI to NAPIQ, GST detoxes NAPIQ but capacity is low. EtoH induces CYP2E1 and exhausts GST= too much NAPIQ=liver failure