BMP: Drug Metabolism 1 Flashcards
Where does the majority of metabolism occur?
The liver cells, in the hepatocytes, in the smooth ER
Describe blood supply to/ from the liver
2 unquie blood supplies
Leaves the Liver - hepatic vein - inferior vena cava
- Aorta: Arotic celiac branch travels to the common hepatic artery
- Portal circaultion
Describe durg administration in relation to the liver
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
What is first pass metabolism
- The metabolism in the liver prior to reaching the systemic circulation
What other route of administration required passage through the portal circulation before the liver?
- Rectally i.e. suppository
- Superior rectal veins – inferior mesenteric – liver
What routes of administration avoid first pass?
Delivery methods not requiring first pass metabolism:
- Sublinguial
- i.v.
- i.m. – into capillaries, veins then heart
- inhalation
Where other than the liver can metabolism occur?
Intestines
- What is bioavailablility
- What does low F mean?
- When would this occur?
- The fraction of drug absorbed into the systemic circulation
- High first pass metabolism therefore low plasma conc of drug
- Two methods where this occurs would be talking a pill by mouth and rectal administration
What are the outcomes of drug metabolism
- Active –> Inactive
- Toxic –> Non Toxic
- Inactive –> Active
- Non Toxic –> Toxic
- Lipid drug –> more water soluble
- What is the major aim of drug metabolism
- Where can drugs be excreted
- 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
Most drugs are small and lipophillic therefore able to pass the intestinal membrane.
- How does the body make drugs more water soluble
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
What are different phases of biotransformation in drug metabolism?
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.
What happens in phase 1 reactions?
What are the main class of enzymes involved?
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
What are examples of phase 1 reactions and enzymes catalysing the reactions
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
Why CYP450 enzymes name?
- 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
What happens during reactions catalysed by CYP450 oxidase enzymes?
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+
Notes on Phase 1 oxidative catalytic cycle
NOT EXAMINABLE
Catalytic Cycle
- •Drug oxidation requires:
- –Cytochrome P450
- –Cytochrome P450 reductase
- –NADPH
- –Molecular oxygen
•The cycle involves four steps:
- Oxidized (Fe3+) cytochrome P-450 combines with a drug substrate to form a binary complex.
- NADPH donates an electron to the cytochrome P-450 reductase, which in turn reduces the oxidized cytochrome P-450-drug complex.
- 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.
- 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.
What is the naming clature of CYP450s?
CYP 2 - family
CYP 2D - subfamily
CYP 2D6 - specific gene
NAMING GENETICALLY BASED - NOT TO DO WITH FUNCTION
What are oxidative reactions not catalysed by CYP450s?
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
Discuss MAO’s
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)
Dsicuss Epoxide hyrolases
- 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.
