(8.1) Intro to Biotransformation, Pharmacogenomics and Clinical Drug Trials (Kruse)

Question 1

What is drug biotransformation?

Answer 1

Enzymatically driven process whereby a substance is changed from one chemical to another

Question 2

What is the general method of eliminating compounds?

Answer 2

Biotransformation into more polar and sometimes larger derivatives

*Polar and water soluble products are more readily excreted by the kidneys

Question 3

What is a prodrug?

Answer 3

An inactive drug that undergoes biotransformation to become an active drug

Question 4

Where does biotransformation primarily occur?

Answer 4

Mostly the liver

Question 5

What is the first pass effect?

Answer 5

The process by which oral drugs undergo extensive biotransformation after absorption prior to entering circulation

Question 6

Drugs administered __________ do NOT undergo first-pass biotransformation

Answer 6

Paraenterally

Question 7

As a general rule:

Phase I reactions….

Phase II reactions…

Answer 7

Phase I reactions = INACTIVATION of the drug

Phase II reactions = ENHANCES ELIMINATION

Question 8

Describe the mechanism of a phase I reaction

Answer 8

Enzymes convert the parent drug to a more polar metabolite by introducing or unmasking a functional group

Oxidation, reduction and hydrolysis reactions

Question 9

Describe the mechanism of phase II reactions

Answer 9

Enzymes form a conjugate of the substrate (phase I product)

Conjugation with endogenous substrates to improve water solubility and increase molecular weight

PHASE II REACTIONS ARE ANABOLIC

Question 10

What are phase I reactions carried out by?

Answer 10

Mixed function oxidases (MFOs)

• Cytochrome P450s
• Flavin-containing monooxygenases (FMO)
• Epoxide hydrolases (mEH, sEH)

Question 11

What is the MOST important of the cytochrome P450 enzymes?

Answer 11

CYP34A

Question 12

What are examples of phase II enzymes?

Answer 12

UGT : UDP-glucuronosyltransferase

GST : glutathione-S-transferase

NAT : N-acetyltransferase

TPMT : Thiopurine methyltransferase

SULT : Sulfotransferase

Question 13

What is the clinical relevance of biotransformation?

Answer 13

Individuals differ in drug distribution and in their rates of drug metabolism and elimination

Question 14

Define:

Pharmacogenetics

Answer 14

The study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity at the genomic level

Question 15

Define:

Pharmacogenomics

Answer 15

The study of the entire genome to assess multigenic determinants of drug response

Question 16

Define:

Polymorphism

Answer 16

A variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population

Question 17

What is the most common disease producing enzyme defect of humans?

Answer 17

Glucose-6-phosphate dehydrogenase deficiency

Question 18

Describe the basic timeline of drug development and clinical trials

Answer 18

Question 19

Define:

No-effect dose

Answer 19

The maximum dose at which a specified toxic effect is not seen

Question 20

Define:

Minimum lethal dose (LD_min)

Answer 20

The smallest dose that is observed to kill any experimental animal under a defined set of conditions

Question 21

Define:

Median lethal dose (LD₅₀)

Answer 21

The dose that kills approximately 50% of the animals