Med Chem Lecture 9-13

Front 1

what is a xenobiotic?

Back 1

foreign compounds not produced by or normally found in an organism

- substances absorbed from environment
- ingested accidental or intentional (food, water, air, therapeutic drugs)

Front 2

what does the body try to do to xenobiotics?

Back 2

tries to convert into inactive metabolites

- some are harmless but many have biological activities

Front 3

termination of biological activity
1. renal excretion

Back 3

-small molecules
-polar or charged molecules
-drugs ionized at physiological pH

Front 4

why is renal excretion not optimal for all drugs?

Back 4

doesn't work well for:
- organic molecules (reabsorbed in nephron) lipophilic, unionized
- compounds with affinity for plasma proteins (bound to albumin/alpha-1-glycoprotein, not filtered out by glomerulus)

Front 5

termination of biological activity

2. metabolism of lipophilic xenobiotics

Back 5

biotransformation of drugs into more polar products ---> excretion

Front 6

functions of metabolism

1. inactivates lipid soluble drugs (or less active)

Back 6

drug-->inactive metabolite-->excretion

Front 7

functions of metabolism

2. increases polarity --> water soluble compounds

Back 7

passive reabsorption of lipid-soluble, unionized drugs

organic compounds often unionized, eg Thiopental

Front 8

functions of metabolism

3. bioactivation (prodrug-->drug)

Back 8

Drug-->active metabolite-->therapeutic action

some drug precursors activated by metabolic pathways

Front 9

functions of metabolism

4. parent drug becomes more toxic-

Back 9

metabolites may have harmful cellular effects

**some endogenous substances made via metabolic pathways
(vit D, cholesterol, steroid hormones)

Front 10

bioactivation pathway

use of L-DOPA to treat parkinsons disease:

Back 10

L-DOPA can be administered with peripheral decarboxylase inhibitor (carbidopa)
- lipid soluble, penetrates BBB
-converted to dopamine in the brain

Front 11

dopamine and parkinsons

Back 11

dopamine with amino group can't go through BBB
only small, non charged can go through BBB (lipophilic)
dopamine is polar, doesn't penetrate BBB
beneficial in parkinsons

Front 12

biotoxic pathway

toxicity of halothane (pathway)

Back 12

halothane-->[halothane]+ --> binds to liver, acts as hapten --> antibodies produced --> hepatitis

Front 13

biotoxic pathway

halothane (stats)

Back 13

20% of patients= mild hepatotoxicity

small % (1/25,000)= immunological response

Front 14

halothane is converted to:

Back 14

trifluoroacetyl (TFA)- protein
adduct
- binds to liver cells, triggers immune response
- potential for severe hepatic necrosis (life threatening, liver transplant)
idiosyncratic- only a few pts w/response

Front 15

drug biotransformation

Back 15

see slide

Front 16

Phase I reactions

Back 16

oxidation, reduction, hydrolysis

converts parent drug into more polar metabolites by introducing a functional group
-OH
-NH2
-SH

Front 17

Phase I reactions

1. oxidation

Back 17

- aromatic hydroxylation
- aliphatic hydroxylation
- dealkylation: O-, N-, S-
- oxidation: N-,S-,P- (converts to S=O...)
- deamination
- desulfuration
- dehalogenation

Front 18

Phase I reactions

2. reduction

Back 18

carbonyls, sulfoxides, N-Oxides, Nitro, Aza, Disulfides, C=C

Front 19

Phase I reactions

3. hydrolysis

Back 19

esters, ethers, C-N bonds, dehydration, decarboxylation

Front 20

Phase I reactions

metabolites are:

Back 20

often inactive

if polar enough, readily excreted

Front 21

Phase II reactions

Back 21

utilizes new functional group to add a highly polar conjugate to metabolite/parent drug

get a free OH- add gluc.. acid- makes it polar and allows excretion

Front 22

Phase II reactions

conjugation

Back 22

-glucuronidation
-sulfation
-methylation
-glutathione conj
-acetylation
-alpha-amino acid conj
** all endogenous substrates

Front 23

Phase II may :

Back 23

skip phase I or proceed it, can go backwards into Phase I

- parent drug contains functional group that can be conjugated

Front 24

Phase II activation of Isoniazid

Back 24

free hydrazide moiety available (NH-NH2)
- conjugated to N-acetyl group (CO-CH3) Phase II

followed by Phase I: hydrolysis adds H2O
= isonicotinic acid + acetylhydrazine

Front 25

multiple metabolites

Back 25

rapidly metabolized drugs are eliminated more quickly than poorly metabolized drugs

see slide

Front 26

multiple metabolites

this effect increased if:

Back 26

parent drug is metabolized into multiple metabolites

Front 27

sites of biotransformation

every tissue is capable of metabolizing drugs
principle organ responsible:

Back 27

1.liver

Front 28

sites of biotransformation

every tissue is capable of metabolizing drugs
responsible to lesser extent:

Back 28

2. GI tract
3. Lungs
4. Skin
5. Kidney's
6. Brain

Front 29

First pass effect:

orally administrated drugs

Back 29

- GI tract and liver (via portal blood)

** barrier for xenobiotics

Front 30

First pass effect:

inhaled drugs

Back 30

- Nasal mucosa and lungs

** barrier for xenobiotics

Front 31

extrahepatic metabolism

many drugs absorbed and immediately delivered to:

Back 31

liver, via portal systme

first pass effect (isoproterenol, morphine)

Front 32

Intestinal metabolism also contributes significantly
characteristics vs liver metabolism:

Back 32

lower enzymatic activity, greater substrate specificity, independently regulated, metabolites produced may differ

** people with compromised liver function rely on this mech.

Front 33

If intestinal metabolism compromised:

Back 33

-plasma drug concentration elevated

-potential drug-drug interactions

Front 34

mechanisms of extrahepatic metabolism

what happens when first pass effect severely limits bioavailability?

Back 34

route of administration may be consideration

Front 35

Factors contributing to intestinal metabolism:

Back 35

1. intestinal flora may catalyze biotransformations
(remove sulfate or glucouronic acid= reabsorption)
2. gastric acid metabolism (penicillin)
3. digestive enzymes
4. enzymes in intestinal walls
5. spontaneous, non-catalytic rxns

Front 36

subcellular locations of metabolism:

Back 36

ER, cytosol, mitochondria, lysosomes, plasma and nuclear envelope membranes

Front 37

Phase I: enzymatic reactions

1. location

Back 37

in lipophilic ER in membranes of liver hepatocytes (90% of liver cells)

RER- protein synthesis
SER- enzymes for oxidative metabolism (ideal for metabolizing hydrophobic drugs)

Front 38

Phase I: enzymatic reactions

2. mixed function oxidases(MFO's)/monooxygenases

Back 38

a. components- cytochrome P450 and P450 reductase(FAD, FMN)

b. cofactors- NADPH (electron donor, H+) nicotinamide adenine dinucleotide phosphate)
molecular oxygen (O2)

Front 39

cytochrome P450 (terminal oxidase)

Back 39

multiple isoforms- has capacity to metabolize a wide range of structurally diverse substrates

Front 40

cytochrome P450 (terminal oxidase)

contains:

Back 40

heme protein

Front 41

cytochrome P450 (terminal oxidase)

reduced form:

Back 41

(ferrous) bind carbon monoxide (CO), absorbs light @ 450 nm

less available than P450 reductase, rate limiting step

Front 42

CYP450's have a slow enzymatic turnover rate

Back 42

- accommodates broad substrate specificity (can manipulate many drugs)
- overlapping substrate specificity leads to drug-drug interactions, binding competition

Front 43

cytochrome P450 (terminal oxidase)

therapeutic drug 1/2 life:

Back 43

3 to 30 hrs, endogenous = sec/min

Front 44

metabolic drug oxidation by P450

1st step

Back 44

oxidized P450 Fe3++ combines with parent drug (RH)--> unreduced form

Front 45

metabolic drug oxidation by P450

2nd step

Back 45

NADPH donates e- to flavoprotein P450 reductase (reduces Fe3++ ---> Fe2++)

Front 46

metabolic drug oxidation by P450

3rd step

Back 46

second electron reduces O2 (activated P450- substrate complex)

Front 47

metabolic drug oxidation by P450

4th step

Back 47

oxygen is transferred to the drug substrate

RH-->R-OH + H2O
both are released, recycles P450
see slide

Front 48

Variations in human liver P450

nomenclature:

Back 48

CYP2D6 (CYP= enzyme, 2= family, D=subfamily, 6=gene#)

Front 49

Variations in human liver P450

multiple enzymes identified via gene arrays, selective inhibitors:

Back 49

- total of 13 isoforms
- 7 most active- responsible for catalyzing bulk of hepatic drug and xenobiotic metabolism

Front 50

50% of prescription drug metabolism in liver=

Back 50

CYP3A4

Front 51

Variations in human liver P450

exogenous drugs

Back 51

carcinogens
pesticides
toxins

Front 52

Variations in human liver P450

endogenous drugs

Back 52

steroids
fatty acids
prostoglandins

Front 53

P450 enzyme induction

repeated administration of substrates induces expression:

Back 53

1. increases protein synthesis

2. reduces rate of degradation

Front 54

P450 enzyme induction

results in accelerated substrate metabolism:

Back 54

- decreases pharmacologic action
- increase activation of prodrugs
- exacerbate metabolic induced toxicity

Front 55

P450 enzyme induction

up-regulation of protein synthesis CYP3A

Back 55

1. drug binds PXR receptor
2. PXR is translocated into nucleus
3. ligand induced dimerization PXR + RXR
4. activation of regulatory elements (promoter)
5. induction of gene expression

mechanism generally conserved in various CYP enzymes

Front 56

P450 enzyme inhibition

certain drugs inhibit P450 enzymes

Back 56

- imidazole containing, bind heme iron
- antibiotics, metabolized and form a complex with the heme iron (catalytically inactive)
- irreversibly inhibit via covalent interactions
- metabolically generated reactive intermediate binds P450 apoprotein, binds heme, causes heme fragmentation (suicide inhibitors)

Front 57

P450 enzyme inhibition

P450 also found outside liver (lung)- CYP2A13

Back 57

metabolizes nicotine from smoke inhalation
- opens ring, forms toxic metabolites
- binds DNA= lung cancer
- people missing this isoform= lower lung cancer rates