Chapter 4: Biotransformation

Question 1

Biotransformation

Answer 1

-Termination of activity – mechanisms besides renal clearance
a. Metabolically converted
b. Some metabolites become active AFTER biotransformation
c. Most metabolic bio-transformations occur at some point between absorption of the drug into the circulation and its renal elimination

-Occurs wherever these cells are present but primarily in the LIVER

Question 2

First Pass Effect

Answer 2

Every time a drug goes through the liver (or any organ with these enzymes) the concentration of the drug is decreased

Question 3

Route of Blood through Liver via Oral intake

Answer 3

GI tract -> absorbed in the local veins -> Hepatic portal vein -> Sinusoids (Hepatocytes) -> Hepatic vein -> Vena Cava -> Systemic circulation

-Leaves through bile via a counter current mechanism

Question 4

Route of Blood through the Liver via Systemic Circulation

Answer 4

Systemic system -> Hepatic Artery -> Sinusoids -> Hepatic Vein -> Vena Cava -> Systemic circulation

Question 5

Phase 1 Reactions

Answer 5

Convert into more polar molecule which are hydrophilic (which helps with excretion)
(Hydrophobic to Hydrophilic)

 Usually adds an -OH, -NH, -SH
 Most drugs inactivated
 Four types: Oxidation (Cytochrome 450), Reduction, Dehydrogenation, Hydrolysis

Question 6

Phase 2 Reactions

Answer 6

Conjugation to an endogenous substrate
 Add -SO4 group or glucose
 Results in higher molecular weight compounds

Question 7

Cytochrome 450s

Answer 7

Phase 1 reaction via Oxidation (loss of electrons)

CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, CYP3A4
- Accounts for 78% of P450s
a. 2B6
b. 2D6
c. 3A4

Question 8

“Wild” Type CYP

Answer 8

Most common form seen in the population

Denoted with Subtype 1
ex. CYP2A11 or CYP3A11

Doesn’t necessarily mean mutants or variants are bad

Question 9

Hepatic Enzyme Induction

Answer 9

May increase amount of P450

• Can enhance synthesis or degradation

a. Drug 2 induces CYP3A4 which inactivates Drug 1
>More inactivation occurring with increased CYP so inactive Drug amount increasing

b. Drug 2 induces 3A4, but this time it activates the Pro-drug (inactive) form into active drug
>More activation occurs with increased 3A4 so increased effect/amount of drug occurs

Question 10

Hepatic Enzyme Inhibition

Answer 10

Decreases amount of P450

Can enhance synthesis or degradation

a. Drug 4 inhibits CYP3A4 which inactivates Drug 1
-Less inactivation occurring with less CYP so inactivation of drug decreases
- (inactive form amount decreases)

b. Drug 4 inhibits 3A4, but this time it activates the Pro-drug (inactive) form into active drug
- Less activation occurs with less 3A4 so decreased effect of drug could occur
- (decreases amount of active form of drug)