lecture 7.4

Question 1

In phase 1 of drug metabolism, what familiy of enzymes are responsible of the rxns (mainly oxidations)?

Answer 1

cytochrome P-450 family of enzymes

Question 2

What are some characteristics of phase 1 reactions of drug metabolism?

Answer 2

1. Usually oxidations
2. Addition of functional groups (e.g., OH, NH2,SH)
3. increase the water-solubility of the compound
4. Generate products that can be biologically active or inactive
5. Generate products that can be toxic or carcinogenic.

Question 3

Apart from cytochrome P-450 family of enzymes, what other enzymes are involved in phase 1 of drug metabolism?

Answer 3

epoxide hydrolase, various esterases and amidases

Question 4

In phase 1 drug metabolism, addition of functional groups on the drugs allows the drug to undergo ___________________ during phase 2 of metabolism.

Answer 4

conjugation

Question 5

What are some characteristics of phase 2 reactions in drug metabolism?

Answer 5

1. Biosynthesis, and require energy in the form of ATP or UTP
2. Generate products that are biologically inactive
3. Conjugation of drug with moieties that are water-soluble
4. Generate products that are water-soluble –> excreted in bile or urine
5. exhibit genetic differences in expression

Question 6

Do phase II reactions of drug metabolism require any energy?

Answer 6

Yes, in the form of ATP or UTP

Question 7

In phase II reactions of drug metabolism, what are some moieties with which conjugation of drug takes place?

Answer 7

glucuronic acid, acetate, sulphate, amino acids, glutathione

Question 8

What property of the drug changes when it undergoes transformation through phase 1 and phase 2 reactions of drug metabolism?

Answer 8

Biotransformation of drugs changes their lipophilicity

–> Drug metabolites more hydrophilic and excreted by kidneys

Question 9

Can phase 2 reactions precede phase 1 reactions?

Answer 9

yes

Question 10

For the enzymes that catalyze phase 1 reaction of drug metabolism, where are they located?

Answer 10

microsomal fraction of homogenized liver

–> microsomal enzyme system

Question 11

Why are cytochrome P-450 enzymes known as hemoproteins?

Answer 11

due to characteristic UV spectra when combined with carbon monoxide

Question 12

Why is there individual variability in hepatic metabolic activity?

Answer 12

as a consequence of variation in the P-450 isozyme composition

Question 13

Apart from genetic makeup of a person, what other factors can influence the absolute and relative amounts and the activity of P-450 isozymes?

Answer 13

environmental agents (e.g., pesticides, cigarette smoke), diseases and drugs.

Question 14

Several different P-450 isozymes have been isolated in humans. The isozymes have different, but overlapping substrate specificities which account for the broad range of endogenous and exogenous compounds (xenobiotics) metabolized by this system.

Answer 14

True

Question 15

What is the definition of biotransformation?

Answer 15

enzyme-catalyzed alteration of drugs by the living organism

Question 16

Can highly lipid-soluble substance such as pentobarbital be excreted through urine?

Answer 16

Yes, BUT it would be extremely slow

Question 17

What 2 forms of metabolims can biotransformation be divided into?

Answer 17

1. hepatic
2. non-hepatic

Question 18

What are some non-hepatic drug-metabolizing systems that have been studied?

Answer 18

intestinal epithelium, lung, and plasma

Question 19

Name a drug that is metablized in plasma (non-hepatic drug-metabolizing systems).

Answer 19

succinylcholine (a muscle relaxant)
–> hydrolyzed by pseudocholinesterase of liver and plasma to succinylmonocholine

Thus, short duration of action

Question 20

Name a drug that is metablized in lung (non-hepatic drug-metabolizing systems).

Answer 20

Angiotensin I converted to angiotensin II

other drugs that are metabolized and inactivated:
Serotonin, norepinephrine, histamine, prostaglandins, steroids

Question 21

Name the caricnogens that are oxidezed by cytochrome P-450 isoenzymes

Answer 21

polycyclic aromatic hydrocarbons

Question 22

Name an endogenous substance that is oxidezed by cytochrome P-450 isoenzymes

Answer 22

fatty acids

Question 23

Apart from oxidation of drugs, what else could cytochrome P-450s be involved with?

Answer 23

steroid biogenesis in the adrenal gland

Question 24

How are proteins classified into different families?

Answer 24

Genes that encode proteins that are less than 36% similarity in their amino acid sequence belong to different families.

Question 25

How many different families of P-450s have been identified in humans?

Answer 25

8

Question 26

What families of P-450s are responsible for drug metabolism?

Answer 26

family I, II, III and IV

Question 27

How similar are P-450s in the same subfamily (i.e. I, II, III)?

Answer 27

70% or more similar

Question 28

Write out the steps involved in mixed-function oxidation reaction pathway of drug metabolism by P-450s

Answer 28

1. drug substrate binds to (Fe3+)P-450 2. NADPH donates e to flavoprotein reductase 3. flavoprotein reductase reduces P-450-drug complex 4. reduced P-450-drug complex combines with O2 5. 2nd e and 2 H ions are acquired from donor system --> oxidized drug and water + regeneration of oxidized P-450

Question 29

define oxidation and reduction

Answer 29

oxidation: loss of electrons reduction: gain of electrons

Question 30

What could be the possible consequences of biotransformation reactions of drugs?

Answer 30

1. inactivation or detoxification of drug/poison 2. precursor activation 3. metabolic activation 4. conversion to metabolites with dissimilar actions 5. conversion to more active products 6. lethal synthesis 7. metabolite may inhibit further metabolism of parent drug

Question 31

What is the difference between 'precursor activation' and 'metabolic activation' as a consequences of biotransformation reactions?

Answer 31

Precursor activation: inactive precursor converted to active metabolite metabolic activation: active drug converted to another pharmacologically active substance

Question 32

Give an example of 'precursor activation' as a consequence of biotransformation reactions.

Answer 32

inactive precursor L-dopa is converted to dopamine

Question 33

Give an example of 'metabolic activation of drug' as a consequence of biotransformation reactions.

Answer 33

codeine is demethylated to morphine

Question 34

Give an example of a drug that is converted to a more active compound after undergoing biotransformation reactions.

Answer 34

cyclophosphamide converted to more active aldophosphamide

Question 35

Does the concentration of a metabolite often far exceed the concentration of the drug?

Answer 35

Yes. For e.g. Orally administered propranolol (心得安) is rapidly converted to 4-hydroxypropranolol, which has a concentration that is several hundred-fold higher than that of propranolol.

Question 36

Give an example of a drug which when metabolized may inhibit further metabolism of parent drug.

Answer 36

phenytoin metabolized to hydroxyphenytoin inhibit hydroxylase system which metabolized phenytoin --> high conc of free form --> toxicity

Question 37

What is the effect of drug dose on rate of metabolism?

Answer 37

low dose: metabolism is first order --> proportional to drug dose higher dose: metabolism is zero order --> constant and independent of drug dose

Question 38

What are some factors that may alter (inhibit or stimulate) drug metabolism?

Answer 38

1. pharmacogenetics --> molecular abnormalities such as alteration in receptor sites or deficiency of enzymes 2. liver disease 3. influence of age 4. enzyme induction and inhibition

Question 39

Name a liver disease

Answer 39

cirrhosis

Question 40

Name some conditions that may indicate liver abnormalities

Answer 40

1. alteration in the serum albumin or bilirubin, and in the prothrombin time 2. skin bruising & bleeding tendency --> decreased production of clotting factors by the liver

Question 41

How could be the activities of microsomal drug-metabolising enzymes be enhanced?

Answer 41

by altering the levels of endogenous hormones such as androgens estrogens progestational steroids glucocorticoids anabolic steroids norepinephrine insulin thyroxine.

Question 42

The accelerated activities of drug-metabolizing enzymes are blocked by substances such as:

Answer 42

ethionine, puromycin, and actinomycin D

Question 43

Name some exogenous substances that may induce the effect of enhancing or suppressing of activities of microsomal drug-metabolizing enzymes

Answer 43

drugs, food preservatives, coloring agents, insecticides, volatile oils, urea herbicides, and polycyclic aromatic hydrocarbons.

Question 44

The volume of distribution of drugs that do not bind to plasma or tissue proteins varies between the extracellullar fluid volume (~15 liters) and the total body water (~45 liters).

Answer 44

True

Question 45

Where is the mixed-function oxidase system or monooxygenase, including P-450, in the liver located?

Answer 45

The hepatic endoplasmic reticulum