Drug Biotransformation

Question 1

What is Biotransformation?

Answer 1

The metabolic alteration of the chemical structure of a drug.
aka: Drug metabolism
Happens through enzymes (usually)

Question 2

What does biotransformation do?

Answer 2

Make a lipophilic compound hydrophilic (preparing it for excretion).
Inactivate drug/toxin.
Activate drug/toxin

Question 3

Consequences of metabolism (4)?

Answer 3

1. Transformation: does NOT deactivate.
2. Deactivation: inactive
3. Makes toxic: reactive
4. Activate an inactive drug: active drug

Question 4

Why is biotransformation important?

Answer 4

1. Lipophilic compounds will not be eliminated unless made hydrophilic.
2. Inactivation of a drug terminates it’s effect.
3. Activating the drug makes it effective.

Question 5

Prodrugs:

Answer 5

must be activated by metabolism to be effective. (AZT, sulindac)

Question 6

Metabolism can make some drugs toxic

Answer 6

Benzo(a)pyrene and aflatoxin

Acetaminophen

Question 7

Acetaminophen toxicity

Answer 7

Higher doses (than recommended) is metabolized to a toxic form in the liver (4 or more g’s in a day).

Question 8

Reactive form of acetaminophen causes:

Answer 8

hepatic necrosis

Question 9

One active form to another:

Answer 9

Diazepam (t 1/2 of 43 hours) to desmethyldiazepam (half-life of 100 hrs)
Terfenadine (toxic, no longer used) becomes fexofenadine (allegra, used).

Question 10

Drug metabolism in liver:

Answer 10

main site of general purpose transformation (most metabolism done here).
Portal circulation: intestines to liver, first pass effect due to this.

Question 11

GI tract metabolism:

Answer 11

• **Enteral administration
  1. The lumen wall: catecholamines
  2. Digestive enzymes: proteins
  3. Acidity in stomach: penicillin breakdown. (non-specific chemical degradation not generally equal to metabolism).
  4. Microorganisms in large intestine.

Question 12

Lung metabolism:

Answer 12

Inhalants and some IV drugs (anesthesia)

Acts as metabolizer and filter.

Question 13

Local metabolism:

Answer 13

Esterases: metabolism of sympathetic drugs.

Some are metabolized by local enzymes and made toxic (MPTP)

Question 14

Ester group

Answer 14

Type of molecular bond that is easily broken.
Have short half-lives.
Some drugs advantages this (heroin becomes morphine).

Question 15

drug biotransformation makes lipophilic drugs hydrophilic so they can be excreted to urine.
Two phases of metabolism:

Answer 15

1. Conversion: opens or adds a hydrophilic or polar site to the drug.
2. Conjugation: adds a hydrophilic molecule to the side of the drug.

Question 16

Phase I: Conversion

Answer 16

Adds a functional group to the molecule: OH, NH2, SH= makes it more polar, prepping for phase II.

• *May make it hydrophilic enough for immediate renal elimination w/out phase II.
• **Take place in smooth microsomes, ER of liver: cytochrome P-450 (or mixed function oxidases, MFO)

Question 17

Cyt-P450

Answer 17

Adds OH to drug, it’s to chemical metabolism what the immune system is to microbial infections (deactivates and excrete a wide variety of compounds).

Question 18

Isozymes of P450

Answer 18

P450 cytochrome is a collection of oxidative enzymes.

Question 19

Phase I reaction via P450:

Answer 19

1. Alliphatic/aromatic hydroxylation: adds OH to C
2. N-oxidation: adds OH to N
3. S-oxidation
4. Dealkylation: adding OH to molecule has it split off H2CO
5. Desulfuration: replace S with an O

Question 20

P450 isosozymes inhibition: responsible for most drug interactions.

Answer 20

Two drugs compete for one isozyme, the one with the higher concentration will block the other from being metabolized.
Called drug inhibition

Question 21

Example of P450 isozyme inhibition:

Answer 21

Erythromycin prevents breakdown of theophylline, allowing Theo to achieve toxic levels.

Question 22

2 most common P450 isozymes

Answer 22

CYP2D6 and CYP3A4

Question 23

Bully drugs

Answer 23

Some drugs are powerful P450 inhibitors and can interfere with many reactions.
Cimetidine, spironolactone, ketoconazole, ritonavir do this

Question 24

Phase II: conjugation

Answer 24

1. Transferases add a hydrophilic moietiy to functional group supplied by phase I.
2. Compounds added: glucuronide (selectively secreted in bile).
3. Or: acetyl group, glutathione, glycine, sulfate, methyl

Question 25

Phase II and acetaminophen toxicity

Answer 25

This is the phase overwhelmed by too much acetaminophen.

Molecule metabolized by P450 to a reactive form.

Question 26

Enzymatic induction

Answer 26

Repeat exposure to drugs and xenobiotics causes an increase in enzyme amount and activity: speeds up metabolism of subsequently administered drugs

Question 27

Example of enzymatic induction

Answer 27

Phenobarbital decreases half-life of ethosuximide from 54 to 29 hours

Question 28

Inducers:

Answer 28

There are not many
About half are antiepileptics (phenob, carbamazepine).
Some environmental compounds (cig smoke, hydrocarbons).
Some herbs (St. John’s Wort)