DRUG BIOTRANSFORMATION

Question 1

These drugs can result in significant drug-drug interaction or DDI because of the compromise of intestinal metabolism.

Answer 1

Felodipine and Cyclosporine A

Question 2

Felodipine acts as _______ and help and lowering high blood pressure

Answer 2

Calcium channel blocker

Question 3

Principal organ of drug metabolism

Answer 3

Liver

Question 4

Other organs that participate in drug metabolism

Answer 4

Kidneys, lungs, skin, brain

Question 5

A term used for drugs that are orally administered, absorbed intact in the small intestine, and transported first via the portal system of the liver.

Answer 5

First-pass effect

Question 6

These orally administered drugs are more extensively metabolized in the intestine than in the liver.

Answer 6

Clonazepam (seizure)
Chlorpromazine (psychotic disorders)
Cyclosporine (immunosuppresant)

Question 7

True or False. First pass effect may limit the bioavailability of orally administered drugs such as lidocaine (anes).

Answer 7

True

Question 8

Some of the enzymes affect drugs…Identify what enzymes affect the following:

1. Penicillin
2. Polypeptides such as insulin
3. Sympathomimetic catecholamines

Answer 8

1. gastric acid
2. digestive enzymes
3. enzymes in the wall of the intestine

Question 9

Most transformations are catalyzed by specific cellular enzymes. At the subcellular level, these enzymes are located in the?

Answer 9

1. endoplasmic reticulum
2. mitochondria
3. cytosol
4. lysosomes
5. nuclear envelope
6. plasma membrane

Question 10

Many drug metabolizing enzymes are located in the ________.

Answer 10

Lipophilic endoplasmic reticulum membranes of the liver and other tissues.

Question 11

When lamellar membranes are isolated by homogenization and fractionation of cells, they reform into vesicles known as

Answer 11

MICROSOMES

• microsomes retain: intact membranes (rer and ser)
• smooth microsomes: responsible for oxidative drug metabolism
• smooth microsomes: contain mixed function oxidases or monooxygenases.

Question 12

Reducing agents required by MFO (monooxygenases)

Answer 12

NADPH and molecular oxygen (Nicotinamide adenine dinucleotide phosphate)

-1 molecule of oxygen is reduced per substrate molecule (one oxygen atom appears in the product and the other in the form of water)

Question 13

2 microsomal enzymes that play key role in oxidation-reduction process

Answer 13

• NADPH-cytochrome P450 oxidoreductase (POR or CPR)

- Cytochrome P450 (P450 or CYP)

Question 14

one mole of this microsomal enzyme contains 1 mol each of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)

Answer 14

-NADPH-cytochrome P450 oxidoreductase (POR or CPR)

Question 15

serves as terminal oxidase; a hemoprotein; multiple forms of this is present in the microsomal membrane;

-its multiplicity is increased by repeated administration of or exposure to exogenous chemicals

Answer 15

Cytochrome P450 (P450 or CYP)

Question 16

In the reduced form of Cytochrome P450 (P450 or CYp), it binds ________ to give complex that absorbs light maximally at 450 nm.

Answer 16

Carbon monoxide

Question 17

Because of its relative abundance, this step has become a rate-limiting step in hepatic drug oxidations

Answer 17

P450 heme reduction

Question 18

Microsomal drug oxidation requires? (4)

Answer 18

1. P450
2. P450 reductase
3. NADPH
4. Molecular Oxygen

Question 19

Step 1 of cytochrome P450 cycle in drug oxidation

Answer 19

Oxidized (Fe+3) P450 combine with a drug substrate and form binary complex.

Question 20

Step 2 of cytochrome P450 cycle in drug oxidation

Answer 20

NADPH donates an electron to the flavoprotein P450 reductase which in turn reduces oxidized P450-drug complex

Question 21

most dominant enzymes

Answer 21

uridine 5′-diphosphate (UDP)-glucuronosyl transferases (UGTs)

Question 22

encode UGT proteins involved in the metabolism of drugs and xenobiotics.

Answer 22

nineteen UGT genes (UGTA1 and UGT2)

Question 23

11 human sulfotransferases (SULTs) catalyze the sulfation of substrates using_________ as the endogenous sulfate donor.

Answer 23

3′-phospho- adenosine 5′-phosphosulfate (PAPS)

Question 24

Also engaged in the metabolism of drugs and xenobiotics, and in that of leukotrienes and prostaglandins, respectively.

Answer 24

Cytosolic and microsomal glutathione (GSH) transferases (GSTs)

Question 25

Leukotrienes

Answer 25

Cytosolic GSH-GSTs

Question 26

Prostaglandins

Answer 26

Microsomal GSH-GSTs

Question 27

Chemicals containing an aromatic amine or a hydrazine moiety (eg, isoniazid) are substrates of

Answer 27

cytosolic N-acetyltransferases (NATs)

Question 28

cytosolic N-acetyltransferases (NATs) encoded by NAT1 and NAT2 genes, which utilize ______ as the endogenous cofactor.

Answer 28

acetyl- CoA

Question 29

Endobiotic, drug, and xenobiotic epoxides generated via P450-catalyzed oxidations can also be hydrolyzed by

Answer 29

microsomal or cytosolic epoxide hydrolases (EHs)

Question 30

Drug conjugation has been believed to be the last step in biotransformation, thus the term “true detoxification”. However, some drugs still do have toxic effects even after phase II rxn. Give certain conjugation reactions that lead to formation of drug toxicity

Answer 30

1. acyl glucoronidation of non-steroidal anti inflammatory drugs
2. O-sulfation of N-hydroxyacetylaminofluorene
3. N-acetylation of isoniazid

Question 31

This action activates the orally active prodrug MINOXIDIL into a very efficacious vasodilator

Answer 31

Sulfation

Question 32

more potent than morphine itself.

Answer 32

morphine-6-glucuronide

Question 33

Safe therapeutic dose for acetaminophen

Answer 33

1. 2 g/day for an adult

* gluco

Question 34

In the absence of intracellular nucleophiles such as GSH, reactive metabolite such as_______reacts with nucleophilic groups of cellular proteins causing hepatocellular damage.

note: it also participates in redox cycling generating REACTIVE OXYGEN SPECIES

Answer 34

N-acetylbenzoiminoquinone

Question 35

Andidotes of acetaminophen

Answer 35

cysteamine and N-acetylcysteine (NAC; Acetadote; Mucomyst)

Question 36

Within how many hours should N-acetylcysteine be admnistered after acetaminophen overdose?

Answer 36

8–16 hours

*administration of GSH is not effective because it does not readily cross cell membrane

Question 37

giving rise to “genetic polymorphisms” in drug metabolism

Answer 37

Genetic factors

Question 38

occurrence of a variant allele of a gene at a population frequency of ≥ 1%, resulting in altered expression or functional activity of the gene product, or both.

Answer 38

true genetic polymorphism