Chap 4 Drug Metabolism

Question 1

Describe First Pass effect:

Answer 1

The oral route of administration entails passage of the drug through:

1. gastric
2. intestinal contents
3. the epithelium and other tissues of the intestinal wall
4. portal blood
5. the liver before it enters the systemic circulation for distribution to the body.

Metabolism by enzymes in any of these tissues, expulsion by drug transporters, and excretion into the bile all may contribute to the first-pass effect of oral administration.

Question 2

Phase I reactions

Answer 2

Reactions that convert the parent drug to a more polar (water-soluble) or more reactive product by unmasking or inserting a polar functional group such as OH, SH, or NH2

Question 3

Phase II reactions

Answer 3

Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate

Question 4

CYP isozymes

Answer 4

Cytochrome P450 enzyme species (eg, CYP2D6 and CYP3A4) that are responsible for much of drug metabolism. Many isoforms of CYP have been recognized

Question 5

Enzyme induction

Answer 5

Stimulation of drug-metabolizing capacity; usually manifested in the liver by increased synthesis of smooth endoplasmic reticulum (which contains high concentrations of phase I enzymes)

Question 6

P-glycoprotein, MDR-1

Answer 6

An ATP-dependent transport molecule found in many epithelial and cancer cells. The transporter expels drug molecules from the cytoplasm into the extracellular space. In epithelial cells, expulsion is via the external or luminal face

Question 7

Examples of phase I drug-metabolizing reaction:

Name reaction type for:

Oxidations, P450 dependent

Answer 7

Oxidations, P450 dependent:

Hydroxylation

N-dealkylatioN

O-dealkylation

N-oxidation

S-oxidation

Question 8

Name Typical Drug Substrates for Phase 1 drug metabolizing reaction types:

Oxidations, P450 dependent

Answer 8

Typical Drug Substrates1. Deamination

2. Amphetamines, barbiturates, phenytoin, warfarin
3. Caffeine, morphine, theophylline
4. Codeine
5. Acetaminophen, nicotine
6. Chlorpromazine, cimetidine, thioridazine
7. Amphetamine, diazepam

Question 9

Examples of phase I drug-metabolizing reaction:

Name reaction type for:

Oxidations, P450 independent

Answer 9

Oxidations, P450 independent

1. Amine oxidation
2. Dehydrogenation

Question 10

Name Typical Drug Substrates for Phase 1 drug metabolizing reaction types:

Oxidations, P450 independent

Answer 10

Oxidations, P450 independent

1. Epinephrine
2. Chloral hydrate, ethanol

Question 11

Phase I drug-metabolizing reactions:

Reductions

(Name 4)

Answer 11

1. Chloramphenicol
2. clonazepam
3. dantrolene
4. naloxone

Question 12

Phase I drug-metabolizing reaction type:

Hydrolyses

Answer 12

Esters

Amides

Question 13

• Typical drug substrates* for
• Phase I drug-metabolizing* reaction type:

Hydrolyses

(Name 7)

Answer 13

1. Aspirin
2. clofibrate
3. procaine
4. succinylcholine
5. Indomethacin
6. lidocaine
7. procainamide

Question 14

xenobiotics

Answer 14

xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism.

It can also cover substances that are present in much higher concentrations than are usual

foreign chemical compounds found in the air, water, and food.

Question 15

Oxidation reaction:

Answer 15

To cause an atom or group of atoms to lose electrons during a chemical reaction

Question 16

Reduction reaction:

Answer 16

Reduction is chemical reaction that involves the gaining of electrons by one of the atoms involved in the reaction.

The term refers to the element that accepts electrons, as the oxidation state of the element that gains electrons is lowered

Question 17

Hydrolysis:

Answer 17

Hydrolysis is a reaction involving the breaking of a bond in a molecule using water.

The reaction mainly occurs between an ion and water molecules and often changes the pH of a solution.

In chemistry, there are three main types of hydrolysis: salt hydrolysis, acid hydrolysis, and base hydrolysis.

Question 18

Conjugation of the drug

Answer 18

The joining of a toxic substance with some natural substance of the body to form a detoxified product for elimination from the body.

Phase II reaction. These reactions involve covalent attachment of small hydrophilic endogenous molecule such as glucuronic acid, sulfate, or glycine to form water-soluble compounds, that are more hydrophilic.

Question 19

Dealkylation:

Answer 19

The removal of alkyl groups from a compound.

Alkyl group is a type of functional group that has a carbon and hydrogen atom present in its structure. The general formula for an alkyl group is CnH2n+1, where n represents a number or integer.

Question 20

Dehydrogenation

Answer 20

Dehydrogenation is a chemical reaction that involves the removal of hydrogen from an organic molecule.It is the reverse of hydrogenation

Question 21

Biotransformation:

Answer 21

Biotransformation of drugs is one such process. It is an important mechanism by which the body terminates the action of many drugs

Question 22

Phase I reactions include ___ type of reactions.

Name each:

Answer 22

total of 4

1. oxidation (especially by the cytochrome P450 group of enzymes, also called mixed-function oxidases),
2. reduction
3. deamination
4. hydrolysis

Question 23

Where are enzymes found:

Name the Organ & Cellular structure

Answer 23

enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver.

Question 24

which P450 isoform is responsible for the greatest number of important reactions

Answer 24

Of the drugs metabolized by phase I cytochrome P450s, approximately:

75% are metabolized by just two:

1. CYP3A4/5
2. CYP2D6

Question 25

What type of reactions are (Phase II ractions) & involve additon of what subgroups

Answer 25

Phase II ractions are *synthetic reactions* that *involve addition (conjugation) of subgroups to —OH, —NH2, and —SH* functions on the drug molecule

Question 26

Name subgroups of Phase II Reactions: name 6:

Answer 26

The subgroups that are added include: 1. gluc- uronate, 2. cetate, 3. glutathione, 4. glycine, 5. sulfate, 6. methyl groups.

Question 27

What are the *phase II drug-metabolizing:* ***reaction types & drug substrates*** Name all 6:

Answer 27

1. Glucuronidation **Sub:** Acetaminophen, diazepam, digoxin, morphine, sulfamethiazole 2. Acetylation **Sub:** Clonazepam, dapsone, isoniazid, mescaline, sulfonamides 3. Glutathione conjugation **Sub:** Ethacrynic acid, reactive phase I metabolite of acetaminophen 4. Glycine conjugation **Sub:** Deoxycholic acid, nicotinic acid (niacin), salicylic acid 5. Sulfation **Sub:** Acetaminophen, methyldopa 6. Methylation **Sub:** Dopamine, epinephrine, histamine, norepinephrine, thiouracil

Question 28

What is the most important organ for drug metabolism ?

Answer 28

liver

Question 29

Biotransformation of a drug may vary markedly among different individuals. This variation is most often due to what two factors :

Answer 29

Genetic or drug-induced differences

Question 30

What is the p*rimary determinant of clearance*, & what must be considered carefully when designing or modifying a dosage regimen.

Answer 30

rate of biotransformation variations in drug metabolism

Question 31

*Coadministration* of certain *agents* may alter the disposition of many drugs, Mechanisms include the following:

Answer 31

1. Enzyme induction 2. Enzyme inhibition 3. Inhibitors of intestinal P-glycoprotein

Question 32

Enzyme induction:

Answer 32

Induction (*increased rate of activity and extent of metabolism*) usually results from *increased synthesis of cytochrome P450 drug-oxidizing* enzymes in the liver as well as the cofactor, heme

Question 33

What are the most common strong inducers of drug metabolism

Answer 33

1. carbamazepine 2. phenobarbital 3. phenytoin 4. rifampin

Question 34

Enzyme inhibition

Answer 34

is a molecule that binds to an enzyme and decreases its activity.

Question 35

Suicide Inhibitors:

Answer 35

is an irreversible form of enzyme inhibition that occurs when an enzyme binds a substrate analog and forms an irreversible complex with it through a covalent bond during the normal catalysis reaction

Question 36

Ex of Suicide Inhibitors: 7

Answer 36

Such agents include: 1. ethinyl estradiol 2. norethindrone, 3. spironolactone, 4. secobarbital, 5. allopu- rinol, 6. fluroxene, 7. propylthiouracil

Question 37

Inhibitors of intestinal P-glycoprotein:

Answer 37

membrane-associated transport protein, an important element of the intestinal epithelium P-glycoprotein contributes to the elimination of many drugs by mediating their direct secretion from the blood into the intestinal lumen

Question 38

Describe the mechanism of *hepatic enzyme induction* : list 3 drugs that are known to cause it:

Answer 38

Induction (increased rate and extent of metabolism) usually results from increased synthesis of cytochrome P450 drug-oxidizing enzymes in the liver as well as the cofactor, heme Liver enlargement in response to *hepatic enzyme induction* is typically associated with hepatocellular hypertrophy and often, transient hepatocyte hyperplasia 1. carbamazepine 2. phenobarbital 3. phenytoin 4. rifampin

Question 39

List 3 drugs that inhibit the metabolism of other drugs.

Answer 39

1. amiodarone, 2. cimetidine, 3. furanocoumarins (present in grapefruit juice)

Question 40

Describe some of the *effects* of smoking, liver disease, and kidney disease on drug elimination.

Answer 40

Smoking is a *common cause of enzyme induction* in the **liver** and **lung** and may *increase the metabolism* of some drugs.

Question 41

Describe the Inhibitors of intestinal P-glycoprotein and its importantce

Answer 41

**P-glycoprotein (P-gp)**, is an important modulator of intestinal drug transport and usually functions to expel drugs from the intestinal mucosa into the lumen, thus contributing to presystemic (first pass) elimination

Question 42

**P-gp** and other members of the **MDR family** are found where:

Answer 42

P-gp and other members of the MDR family are also found in the blood-brain barrier and in drug-resistant cancer cells.

Question 43

P-gp inhibitors

Answer 43

**P-gp** *inhibitors include:* * 1.* *verapamil* 2. *mibefradil* (a calcium channel blocker no longer on the market ) 3. *furanocoumarin* (components of grapefruit juice)

Question 44

Drugs that inhibit intestinal P-gp