Fundamentals Of Medicinal Chemistry Exam 2

Front 1

Drugs that contain carboxylic acid groups (-COOH) can sometimes form esters with a fatty substance present in the body. The metabolite is not readily excreted. Name the fatty substance, and the enzyme that catalyzes the reaction.

Back 1

Cholesterol. Ester hydrolase.

Front 2

Efflux transport of drug metabolite is sometimes called _____________ of drug metabolism.

Back 2

phase III

Front 3

Do all drugs interact only with their respective receptors? Why or why not?

Back 3

No. May have structure similar to interacting at other receptors so good chance it will also interact somewhat at other receptors.

Front 4

Name one way an alcohol might be metabolized.

Back 4

Oxidation

Front 5

State how biotransformation usually affects the physio-chemical properties of the drug.

Back 5

Increases the water solubility.

Front 6

Give the definition of Phase I reactions of drug molecules.

Back 6

Phase I reactions introduce or uncover a functional group/s in the drug molecule.

Front 7

Give 5 examples of classes of chemicals that are considered xenobiotics.

Back 7

Therapeutic drugs
Food additives
Drugs of abuse
Pesticides
Household chemicals

Front 8

Explain who it is important as pharmacists and as a member of the health care team, to understand drug biotransformation.

Back 8

The rate and extent of drug biotransformation will determine the duration of action of a drug. This will affect how often the drug is taken.

Front 9

Enzymes of biotransformation often have _____ affinity for their drug substrates.

Back 9

low

Front 10

There are many individual forms of cytochrome P450 enzymes in the human liver. State one feature that all of these enzymes have in common and why it is important.

Back 10

All contain a heme-iron prosthetic group. This is the site of oxygen binding and drug oxidation.

Front 11

State one way in which individual cytochrome P450 enzymes differ from one another and what effect does this difference have on how each of the enzymes work.

Back 11

The individual cytochrome P450 enzymes have different primary amino acid sequences. Each has a somewhat different substrate selectivity.

Front 12

Considering the major prescription drugs today, which phase I enzyme is the most important in their biotransformation?

Back 12

CYP 3A4

Front 13

Briefly define phase II reactions.

Back 13

A functional group in the drug (or any drug metabolite) is combined with a small, usually polar and water-soluble, endogenous molecule to form a conjugated metabolite. The phase II metabolite is often anionic at physiological pH and readily excreted.

Front 14

Glucuronidation and sulfation pathways often compete for the same substrat. State the conditions under which glucuronidation may be expected to be the predominant pathway.

Back 14

If the dose of the drug leads to a high concentration in the liver, then glucuronidation is expected to predominate. This is because although UGT has a low affinity for drugs, it has a high capacity and also because the co-substrate UDP-GA is abundant and readily synthesized. In contrast, sulfonation is often saturated because of a low availability of PAPS and the difficulty of synthesizing PAPS.

Front 15

Drugs that contain aliphatic hydroxyl groups (-OH) can sometimes form esters with a fatty acid substance present in the body. The metabolite is not readily excreted. Name the fatty substance, and the enzyme that catalyzes the reaction.

Back 15

Fatty acid. Ester hydrolase.

Front 16

____________ adds to another molecule or functional group.

Back 16

Conjugation

Front 17

____________ adds water.

Back 17

Hydrolysis

Front 18

____________ adds oxygen in various forms.

Back 18

Oxidation

Front 19

____________ adds alkyl groups.

Back 19

Alkylation

Front 20

Explain what is meant by the term "drug biotransformation."

Back 20

Conversion of a drug to a metabolite by an enzymatic process.

Front 21

Give an example of a xenobiotic.

Back 21

Therapeutic drug, food additive, small organic molecule not needed for physiological purposes, pesticide, or an environmental pollutant

Front 22

What physio-chemical property of a drug is usually changed following the process of drug biotransformation?

Back 22

The water solubility of the drug is usually increased following biotransformation.

Front 23

Phase I reactions ____________ or ___________ functional groups in drug molecules.

Back 23

introduce. uncover.

Front 24

State another name for phase II reactions of drug biotransformation.

Back 24

Conjugation reactions

Front 25

True/False
Enzymes of drug biotransformation usually have a very high affinity for their substrates.

Back 25

False. low.

Front 26

The most abundant form of cytochrome P450 in the human liver is CYP3A4. Explain what this terminology means.

Back 26

CYP is the abbreviation for cytochrome P450, a heme-thiolate protein. 3 is the family this particular protein belongs to. To be in a family, proteins must have an amino acid primary sequence that is at least 40% similar to other family members. A is the sub-family. To be in a sub-family, proteins must be at least 55% similar. 4 is the actual P450 proteins with >97% sequence identity and are considered the same protein.

Front 27

Name 4 functional groups that are commonly found in drug molecules and that can undergo hydrolysis to uncover new functional groups.

Back 27

Ester
Amide
Peptide
Epoxide

Front 28

State three phase II pathways that are quantitatively most important for widely used therapeutic drugs. Which of these three pathways is likely to be rate-limited by the availability of co-substrate in the cell?

Back 28

Glucuronidation
Sulfonation - Likely to be limited by co-substrate availability in the cell
Glutathione conjugation

Front 29

The endogenous tripeptide ______________ reacts with electrophilic centers in drug molecules. The product is not excreted directly, but is further metabolized in ________________ additional steps (not including the first step) to an N-acetyl-cysteine conjugate, also known as a _______________ acid.

Back 29

glutathione
three
mercapturic

Front 30

The usual effect of xenobiotic biotransformation is to convert a _____________ drug into a water-soluble metabolite that is more readily _______________ from the body.

Back 30

lipophilic
excreted

Front 31

Phase I reactions ______________ or ______________ functional groups in drug molecules.

Back 31

introduce
uncover

Front 32

As well as the protein, what other components of the enzyme cytochrome P450 are vital for the enzyme to have catalytic activity.

Back 32

Iron
Heme prosthetic group

Front 33

Define phase II biotransformation.

Back 33

Combine functional groups in the drug with small, usually polar molecule.

Front 34

The co-substrate for acetylation is _______________ and the cosubstrate for methylation is ________________.

Back 34

acetyl CoA
S-adenosyl-methionine (SAM)

Front 35

Drugs that contain electrophilic centers can be detoxified by conjugation with the tripeptide _________________. These conjugates must be further metabolized to _________________ _________________

Back 35

glutathione
mercapturic acids

Front 36

Two drugs that contain hydroxyl groups are orally active. The effective dose for one drug is 1500 mg and the effective dose for the other drug is 5 mg. Predict the likely urinary metabolites of each drug. What factors with influence which metabolites are formed?

Back 36

1500 mg - Glucuronide
5 mg - Sulfate
Affinity of drugs for sulfotransferase versus UDP-glucuronyltransferase.
Availability of cosubstrate, PAPS and UDP-GA. PAPS - Limited availability, difficult to synthesize. UDP-GA - High availability, easy to synthesize.

Front 37

Name a phase 2 reaction that results in a less water soluble product than the parent drug.

Back 37

Methylation, fatty acid conjugation or cholesterol conjugation.

Front 38

Name four biological processes that are influenced by chemical structure (lipid solubility)

Back 38

Absorption
Metabolism
Excretion
Biological activity

Front 39

Do all drugs interact only with their respective receptors?

Back 39

No.

Front 40

A xenobiotic that is ________________ is readily absorbed after oral administration, but has to be converted to a more _________________ metabolite to be eliminated from the body.

Back 40

Lipophilic
Hydrophilic

Front 41

In what way do phase I reactions alter drug molecules?

Back 41

Introduce or uncover a functional group

Front 42

In phase II biotransformation reactions, a drug's _________________ group is combined with a small, usually polar _________________ molecule. The metabolic product is often an _________________ at physiological pH.

Back 42

functional
endogenous
anion

Front 43

The co-substrate for glucuronidation is ___________________ and the co-substrate for methylation is ___________________.

Back 43

UDP-glucuronic acid
S-adenosylmethionine.

Front 44

What general physio-chemical property do drug molecules that are effective orally share?

Back 44

They are lipophilic

Front 45

What is the overall effect of biotransformation pathways on this property?

Back 45

Biotransformation increases water solubility and decreases lipid solubilty

Front 46

Briefly define phase I and phase II biotransformation reactions.

Back 46

Phase I reactions introduce or uncover function groups.
Phase II reactions combine the drug's functional group with a small, usually polar, endogenous molecule.

Front 47

State two ways in which drug-metabolizing enzymes are different from enzymes involved in intermediary metabolism.

Back 47

Broad substrate specificity. Low affinity for the enzyme.

Front 48

The co-substrate for sulfation is ______________ and the co-substrate for acetylation is _________________.

Back 48

PAPS
acetyl CoA

Front 49

The tripeptide ___________________ is important in the phase II detoxification of electrophilic centers in drugs. An example of an electrophilic center is the ____________________ group. This reaction is catalyzed by the enzyme ___________________. The conjugate formed by this reaction is not excreted itself, but is further metabolized to a __________________ __________________, which is readily excreted because it is anionic at physiological pH.

Back 49

glutathione
alkyl halide, epoxide, or quinone imine
glutathione S-transferase
mercapturic acid