Metabolism

Question 1

Discuss competition vs sequential metabolism

Answer 1

Common metabolic reactions include oxidation, reduction, hydrolysis + conjugation

Sequential = drug undergoes metabolic (primary) process, becomes metabolite then undergoes further (secondary) metabolism

e.g. oxidation, reduction + hydrolysis are followed by conjugation

Question 2

Discuss phase 1 vs phase 2 metabolism

Answer 2

Phase 1 = oxidation, reduction + hydrolysis

Phase 2 = conjugation (not always happen)

Phase 1 reactions prepare drug for phase 2

Not all drugs go through phase 2

Question 3

What is the main type of phase 1 metabolism?

Answer 3

Cytochrome P450-Dependent Mixed-Function Oxidation (MFO) Reactions

Catalyses the oxidation of literally thousands of structurally diverse drugs and chemicals

Usually the metabolised molecules have a reasonably high degree of lipophilicity

Question 4

How do we name CYP P450 enzymes?

Answer 4

Nomenclature is based on genetic sequence familarity

Family = 40% similarity

Sub-family 70% similarity

Question 5

What is the major sub-family Cytochrome P450 enzymes in human livers?

Answer 5

CYP3A family

Metbolises many drugs in the intestinal wall and liver

Major player in FPM (highest activity in small intestine)

Major form is CYP3A4 - variation os genetics-based

Question 6

What oxidation reaction involve CYP450

Answer 6

Aromatic hydroxylation

Aliphatic hydroxylation

Epoxidation

Dealkylations

Oxidative deamination

Dehalogenation

N-oxidation

S-oxidation

Phosphothionate oxidation

Question 7

What is the product of phase 2 metabolism?

Answer 7

Water-soluble product that can be excreted in bile or urine

Question 8

What is the most common conjugation reaction?

Answer 8

Glucoronidation (conjugation with D-glucoronic acid) - major route of sugar conjugation

UDP-glucuronosyltransferase is an enzyme (UGT); UDP-glucuronic acid is a co-factor

Question 9

What are the consequences of enterohepatic circulation?

Answer 9

Prolonged half-life

Prolonged pharmacological action

Second peak on plasma-conc time profile after oral admin.

Question 10

Whe does metabolism take place?

Answer 10

The main organ is the Liver - both phase 1 and 2

But, other organs are involved (brain, skin, nlood, GIT ETC.)

Question 11

What does drug localisation + metabolism depend on?

Answer 11

Physicochemical properties of the drug (pKa, lipid solubility, MW)

Chemical composition of a metabolising organ

Presence of specific uptake mechanisms (transporters)

Question 12

Where does metabolism occur in the cell?

Answer 12

2 important organelles are:

• endoplasmic reticulum
• cytosol

Phase 1 oxidative enzymes are in endoplasmic retiiculum along with the phase 2 enzye glucoronosyl transferase

Phase 2 enzymes are found in the cytoplasm

Question 13

What is extraction ratio?

Answer 13

The extraction ratio of an organ of elimination (e.g. the liver or the kidneys) can be viewed as the organ’s relative efficiency in eliminating the drug from the systemic circulation over a single pass through the organ

E = 1 - C_V/C_A

Question 14

How do you calculate hepatic clearance?

Answer 14

CL_H = Q_H = E_H

Q_H = sum of hepatic portal venous flow draining GIT + hepatic arterial blood flow

Q_H = 1.4l/min

CL_H = metabolism, bile secretion, or both

Question 15

What is intrinsic clearance?

Answer 15

Measure for intrinsic hepatocellular elimination activity

The rate of elimination within the cell depends on the intracellular unbound concentration (see previous slide)

Question 16

For a drug with high extraction value EH > 0.7

Answer 16

• Changes in QH will significantly change hepatic clearance
• Changes in protein binding and CLint will not cause significant changes in hepatic clearance

Question 17

For a drug with low extraction value EH <0.3

Answer 17

Changes in QH will not cause significant changes hepatic clearance

Changes in protein binding and CLint will significantly alter hepatic clearance

Unbound drug affects clearance (available for elimination)

Question 18

What is first pass metabolic loss?

Answer 18

Metabolism during the first passage across the intestinal wall and through the liver reduces the amount reaching the general circulation. The drug is then said to undergo first-pass metabolic loss (or first-pass metabolism)

High hepatic extraction ration = low oral bioavailability