BMP: Drug Metabolism 1

Question 1

Where does the majority of metabolism occur?

Answer 1

The liver cells, in the hepatocytes, in the smooth ER

Question 2

Describe blood supply to/ from the liver

Answer 2

2 unquie blood supplies

Leaves the Liver - hepatic vein - inferior vena cava

1. Aorta: Arotic celiac branch travels to the common hepatic artery
2. Portal circaultion

Question 3

Describe durg administration in relation to the liver

Answer 3

IV - reaches rest of body before liver

Sublingual - Reaches rest of body before liver. E.g nitroglycerin helps dilate some blood vessels and increases blood supply to the heart

Orally - intestines – portal vein – Liver – pre-systemic circulation

Question 4

What is first pass metabolism

Answer 4

• The metabolism in the liver prior to reaching the systemic circulation

Question 5

What other route of administration required passage through the portal circulation before the liver?

Answer 5

• Rectally i.e. suppository
• Superior rectal veins – inferior mesenteric – liver

Question 6

What routes of administration avoid first pass?

Answer 6

Delivery methods not requiring first pass metabolism:

• Sublinguial
• i.v.
• i.m. – into capillaries, veins then heart
• inhalation

Question 7

Where other than the liver can metabolism occur?

Answer 7

Intestines

Question 8

1. What is bioavailablility
2. What does low F mean?
3. When would this occur?

Answer 8

1. The fraction of drug absorbed into the systemic circulation
2. High first pass metabolism therefore low plasma conc of drug
3. Two methods where this occurs would be talking a pill by mouth and rectal administration

Question 9

What are the outcomes of drug metabolism

Answer 9

• Active –> Inactive
• Toxic –> Non Toxic
• Inactive –> Active
• Non Toxic –> Toxic
• Lipid drug –> more water soluble

Question 10

1. What is the major aim of drug metabolism
2. Where can drugs be excreted

Answer 10

• Our main strategy is to make drug molecules more water soluble (i.e. hydrophilic). This is to allow the body to excrete the metabolites, via the kidneys, in the urine.
• Some metabolites are excreted in faeces, via lungs, or in sweat
• Although most drug metabolism is to deactivate pharmacologically active compounds, there is some bioactivation, Prodrugs

Question 11

Most drugs are small and lipophillic therefore able to pass the intestinal membrane.

1. How does the body make drugs more water soluble

Answer 11

By oxidation of C,N or S atoms

Oxidation is an increase in the number of bonds an atom has to oxygen, or a redcution in the number of bonds an atom has to hydrogen. It is also clases as a loss of electrons

Question 12

What are different phases of biotransformation in drug metabolism?

Answer 12

Phase 1 reactions:

• •Reactions where a new functional group is introduced to the drug (often Oxygen) or a polar functional group unmasked.

Phase 2 reactions:

• Reactions where a functional group in the drug is masked by addition of another molecule (conjugation reaction).

Phase 3 reactions:

• A system of efflux pump molecules which can exclude drugs from the drug almost as soon as the are absorbed.

Question 13

What happens in phase 1 reactions?

What are the main class of enzymes involved?

Answer 13

Phase 1 Reactions: Oxidases

• Convert parent compound into a more polar (=hydrophilic) metabolite by adding or unmasking functional groups (-Os, -OH, -SH, -NH2, -COOH, etc.)
  
  • Often these metabolites are inactived
  • May be sufficiently polar to be excreted readily

BUT

• May often activate compounds
  
  • More toxic metabolites
  • Anticancer drugs

Question 14

What are examples of phase 1 reactions and enzymes catalysing the reactions

Answer 14

Phase 1 catalysed enzyme reactions

Oxidations:

• Cytochrome P450 monooxygenase system
• Flavin-containing monooxygenase system
• Alcohol dehydrogenase
• Aldehyde dehydrogenase
• Monoamine oxidase

Reductions:

• NADPH-cytochrome P450 reductase
  
  • Reduced (ferrous) cytochrome P450

Hydrolysis:

• Esterases and Amidases
• Epoxide hydrolase

Question 15

Why CYP450 enzymes name?

Answer 15

• CYP450 oxidase enzymes contain a haem group
• Haem binds O2 BUT also CO
• When HAEM bind CO maximum spectra it absorbs is 450nm hence the name

Question 16

What happens during reactions catalysed by CYP450 oxidase enzymes?

Answer 16

O2 + Drug = DrugOH +HO

• But where did the H ions come from? - NADPH
• NADPH acts as a reducing agent i.e. It loses an electron and other molecules gain an electron
• If it loses an electron it is being oxidised itself at the end we form NADPH+

Question 17

Notes on Phase 1 oxidative catalytic cycle

NOT EXAMINABLE

Answer 17

Catalytic Cycle

• •Drug oxidation requires:
• –Cytochrome P450
• –Cytochrome P450 reductase
• –NADPH
• –Molecular oxygen

•The cycle involves four steps:

1. Oxidized (Fe3+) cytochrome P-450 combines with a drug substrate to form a binary complex.
2. NADPH donates an electron to the cytochrome P-450 reductase, which in turn reduces the oxidized cytochrome P-450-drug complex.
3. A second electron is introduced from NADPH via the same cytochrome P-450 reductase, which serves to reduce molecular oxygen and form an “activated oxygen”-cytochrome P-450-substrate complex.
4. This complex in turn transfers “activated” oxygen to the drug substrate to form the oxidized product. The potent oxidizing properties of this activated oxygen permit oxidation of a large number of substrates.

Question 18

What is the naming clature of CYP450s?

Answer 18

CYP 2 - family

CYP 2D - subfamily

CYP 2D6 - specific gene

NAMING GENETICALLY BASED - NOT TO DO WITH FUNCTION

Question 19

What are oxidative reactions not catalysed by CYP450s?

Answer 19

Oxidation reactions NOT catalyzed by Cytochrome P450:

• Flavin containing monoxygenase system
  
  • Present mainly in liver but some is expressed in gut and lung
  • Located in smooth endoplasmic reticulum
  • Oxidizes compounds containing sulfur and nitrogen
  • Uses NADH and NADPH as cofactors
• Alcohol dehydrogenase (cytosol)
• Aldehyde oxidation (cytosol)
• Xanthine oxidase
• Amine oxidases
  
  • Monoamine oxidase (nerve terminals, mitochondria)
  • Diamine oxidase found in liver microsomes
    
    • Primarily endogenous metabolism

Question 20

Discuss MAO’s

Answer 20

Monoamine Oxidases (MAO):

• •Catalyze oxidative deamination of endogenous catecholamines (adrenaline)
• •Located in nerve terminals and peripheral tissues
• •Substrates for catecholamine metabolism found in foods (tyramine) can cause a drug/food interaction
• •Inhibited by class of antidepressants called MAO inhibitors
• (Inhibition of MAO isoforms in the CNS also effects levels of serotonin - Tranylcypromine)
• These drugs can cause severe or fatal drug/drug interactions with drugs that increase release of catecholamines or inhibit their reuptake in nerve terminals (Meperidine, pentazocine, dextromethorphan, SSRI antidepressants)

Question 21

Dsicuss Epoxide hyrolases

Answer 21

• Epoxide hydrolase (EH) catalyzes the trans-addition of water to alkene epoxides and arene oxides, which can form during Phase I (CYP/COX).
• There are 5 distinct forms of EH in mammals:
• Microsomal epoxide hydrolase (mEH)
• Soluble epoxide hydrolase (sEH)
• Cholesterol epoxide hydrolase
• LTA4 hydrolase
• Hepoxilin hydrolase
• mEH and sEH hydrolyze xenobiotic epoxides while the latter 3 hydrolases act on endogenous substrates.
• Epoxides are often produced during CYP oxidation and can react with DNA and protein. EH primarily acts as a detoxification enzyme and can rapidly convert these potentially toxic metabolites to their corresponding dihydrodiols. However, sometimes EH hydrolysis can lead to bioactivation

•

•EH enzymes are found in virtually all tissues, including liver, testis, ovary, lung, kidney, skin, intestine, colon, spleen, thymus, heart and brain.