Drug Metabolism

Question 1

Metabolism

Answer 1

chemical modification of compounds by enzymes

Question 2

What is the predominate site of metabolism? Explain

Answer 2

Liver

1. Smooth ER of liver
2. High concentration of drug metabolizing enzymes
3. First organ perfused by compounds absorbed in the gut

Question 3

Oral bioavailability

What is it influenced by?

Answer 3

Fraction of total dose that reaches systemic circulation

1. solubility
2. membrane permeability
3. P-gp efflux (these transporters actively pump drug out of cell)
4. Presystemic first pass metabolism

Question 4

Phase I of drug metabolism

Answer 4

chemical modification (biotransformation) including oxidation, hydroxylation, etc. to introduce new functional group of expose group for Phase II reactions

mediated largely by P450

Question 5

Phase II of drug metabolism

Answer 5

conjugation of polar group (e.g. acetyl, sulfate, etc.) with drug

drug conjugate displays increased water solubility and decreased lipid solubility

Question 6

Roles of drug metabolism

Answer 6

1. Termination of xenobiotic action
   - bioinactivation
   - detoxification
   - elimination
2. Bioactivation
   - prodrugs
   - toxification

Question 7

Bioinactivation

Answer 7

The drug metabolite(s) may be less active or completely inactive. The active site affinity for metabolites are frequently much lower than the parent compound

Question 8

How is metabolism helpful in elimination?

Answer 8

Metabolism increases the polarity of drug metabolism, thereby:

• decreasing lipid solubility
• increasing water solubility
• –> increases ability to excrete drug

Question 9

Prodrugs

Answer 9

The drug metabolite(s) may be more active than the parent compound, or the parent compound may require activation for biological activity

Question 10

What molecules do CYP450s use in oxidation?

Answer 10

NADPH and oxygen

Question 11

Important structural features of CYP450s?

Answer 11

1. Heme group - iron group catalyzes oxidation
2. Membrane bound
3. Entry and exit pathways - determine specificity b/c determine what can fit

Question 12

P450 reductase

Answer 12

protein associated with P450 in the CYP450 system; contains two prosthetic groups (FAD, FMN); serves as an electron transport protein

Question 13

CYP nomeclature

Answer 13

Example: CYP2D6 * 1A

2 - familiy - 40% identity
D - subfamily - 50% identity
6 - individual gene
1A - allele

Question 14

1/3 of all drugs are metabolized by

Answer 14

CYP3A4

Question 15

1/5 of all drugs are metabolized by

Answer 15

CYP2D6

Question 16

Catalytic center

Answer 16

Active site of CYP contains an iron-heme cofactor

Iron is coordinated to four N atoms of the heme, to one thiolate ligand derived from cysteine, and in the native state to a water molecule

Question 17

Every CYP is in principle able to catalyze the same metabolic reactions, BUT …?

Answer 17

topography of protein binding site and steric hindrance of the access to the catalytic heme group are important factors for drug metabolism

Question 18

Which intrinsic factors determine if and to which extent a chemical group of compound is metabolized?

Answer 18

• can compound enter binding site?
• Orientation, position, and conformation of ligand binding
• Strength of binding
• intrinsic reactivity
• accessibility of chemical group

Question 19

What types of molecules have a strong affinity to the heme iron?

Answer 19

Molecules with nitrogen

Question 20

Induction

Answer 20

Drugs bind to transcription factor proteins that induce transcription of CYP genes –> increased metabolism

Question 21

Drug-drug interaction definition

Answer 21

DDI occur when the efficiency or toxicity of a drug is altered by the co-administration of another drug, food or chemical

Question 22

What are the most common phase II enzymes?

Answer 22

UGT - [UDP]-glucouronosyl transferases