drug metabolism

Question 1

what is drug metabolism?

Answer 1

enzymatic conversion of drug into another chemical entity

Question 2

is drug metabolism saturable process?

Answer 2

yes - as protein dependant

Question 3

what are drug-metabolising organs?

Answer 3

liver = most important
also: kidney, gut mucosa, lungs & skin

• reduces bioavailability of drugs when administered orally

Question 4

what is bioavailability (F)?

Answer 4

• amount of drugs that eventually reaches systemic circulation (and hence available for drug action on target) of an administered dose of the drug
• we visualise as a %
• helps us come up with dose that reaches our therapeutic level

Question 5

how do you calculate bioavailability (F)?

Answer 5

quantity of drug reaching systemic circulation (AUC) / quantity of drug administered (dose)

Question 6

how can bioavailability vary?

Answer 6

can vary depending on route of administration (IV or orally)

Question 7

why does pharmocokinetic graph for oral dose have peak then drop? and why does IV just have one big straight line going down?

Answer 7

oral = has absorption phase so it peaks then eliminates
IV = has no absorption so straight line leading down from x-axis

Question 8

what metabolism occurs if drug given orally?

Answer 8

must go through first pass metabolism and then once drugs in liver 2 phases

Question 9

what is phase 1 reaction of metabolism?

Answer 9

involves oxidation (common), reduction (less common), hydrolysis

Question 10

what is oxidation in phase 1 reaction of metabolism?

Answer 10

• accomplished by cytochrome P450 enzymes, microsomal haem proteins.
• During oxidation the drug molecule incorporates one atom of O2 to the drug to form a hydroxyl group
• Cytoplasmic enzymes can metabolise the drug
• general idea is to increase water solubility so more likely to leave the body

Question 11

what is hydrolytic reaction in phase 1 reaction in metabolism?

Answer 11

• ester and amide bonds are susceptible to hydrolysis
• Usually form chemically reactive metabolites that can be pharmacologically active and/or toxic

hydrolysis example = aspirin
- hydrolysis often makes them more water-soluble for elimination

Question 12

how can phase 1 produce harmful effects? (like paracetemol overdose)

Answer 12

basically the molecule made in phase 1 can be detoxified and make safe substance or it can change and cause tissue damage (often toxic intermediates)

• phase 2 usually conjugates it making detoxified and physiologically inert
• but if overdose (on paracetemol) glutathione (detoxified molecule) can get saturated so can’t conjugate so toxic metabolate accumulates and attaches to cells & goes to liver = liver toxicity

Question 13

what are cytochrome P450 enzymes?

Answer 13

haem proteins that comprise a large superfamily
- CYP1,2, 3 are involved in drug metabolism in human liver

Question 14

how is P450 activity related to drug response?

Answer 14

P450 activity is genetically determined = if lack P450 activity then adverse reactions = if high levels of P450 activity then reduced drug action

• other drugs can interact and induce activity

Question 15

what is phase 2 reaction in metabolism?

Answer 15

(addition of naturally present molecules in body to the drug)
- involve the combination of the drug with one of several polar molecules to form a water-soluble metabolite
- Conjugation usually involve the reactive group produced by Phase I
- Usually terminates all biological activity

Question 16

how are conjugated produces from phase 2 metabolism excreted?

Answer 16

Conjugated produces can be readily excreted via the kidney

Question 17

what is an example of a drug that can go straight to phase 2 metabolism?

Answer 17

codeine = an agonist (G-coupled receptor)
it can be converted into morphine in body