drug metabolism

Question 1

what is the overall goal of phase 1 and 2 metabolism?

Answer 1

increase water solubility of a drug

Question 2

where are cytochrome P450’s found?

Answer 2

liver, intestine, colon, kidneys

Question 3

what part of the haem unit allows for the activation of oxygen?

Answer 3

exchange between Fe2+ and Fe3+

Question 4

what process in metabolism creates the electrons required?

Answer 4

reduction of NADPH

Question 5

describe the structure of cytochrome P450 enzyme proteins?

Answer 5

contains helices I and L which contact the haem unit, and helices B and I which contact the substrate, the iron in the haem unit has an octahedral coordination state imbedded inside a porphyrin ring, water bound to the haem ring is replaced by oxygen during metabolism

Question 6

bullet point the CYP450 cycle?

Answer 6

starting with: CYP450 Fe3+
1) substrate binds
2) reduction of NADPH provides an electron
3) CYP450 Fe2+ binds to drug
4) oxidation forms CYP450 Fe3+ bound to drug with oxygen
5) reduction of NADPH form CYP450 Fe3+ with two oxygens, proton is added to form H2O and is released
6) drug and substrate are released
back to the beginning

Question 7

what factor makes a good substrate for phase 1 metabolism?

Answer 7

high logP

Question 8

what is logP?

Answer 8

a measure of lipophilicity

Question 9

what 2 processes are also a part of phase 1 metabolism?

Answer 9

dealkylation and oxidative deamination

Question 10

explain oxidative deamination and what group is needed on the molecule for it to work?

Answer 10

addition of oxygen and removal of ammonia or an amine, must have an amino group with a hydrogen attached to the same carbon

Question 11

name the 6 processes of phase 2 metabolism?

(always give something good at mothers-day)

Answer 11

acetylation
glucuronidation
sulfonation
glutathione conjugation
amino acid conjugation
methylation

Question 12

explain the process of glucuronidation?

Answer 12

co enzyme UDP glucuronic acid is synthesised and undergoes a stereochemical change to produce B-glycoside glucoronate conjugates which are highly water soluble

Question 13

explain the process of sulfonation, and what the two types of enzymes are for?

Answer 13

sulfonotransferases (SULTS) transfer sulphates from PAPS to the substrate making it more water soluble, SULT1 is for phenolic compounds and SULT2 is for alcohols

Question 14

explain the process of acetylation?

Answer 14

N-acetyltransferases (NAT1 and NAT2) catalyse the replacement of hydrogen with an acetyl group (CH3C=O)

Question 15

what makes a good substrate for N-acetyltransferases?

Answer 15

weak amines with a low logP

Question 16

explain the process of glutathione conjugation?

Answer 16

glutathione S transferases (GST’s) use an Sn2 reaction to oxidate the thiol and form a conjugate base

Question 17

explain the process of amino acid conjugation?

Answer 17

acetyl coenzyme A conjugates carboxylic acids with amino acids via the formation of an amide bond

Question 18

explain the process of methylation?

Answer 18

uses SAM cofactors in an Sn2 pathway to add a methyl group creating a more water soluble compound

Question 19

what is the role of carboxylesterases?

Answer 19

hydrolyse esters via nucleophilic acyl substitution

Question 20

how do you calculate dosing rate?

Answer 20

( target plasma concentration x clearance ) / bioavailability

Question 21

give an example of a pro drug?

Answer 21

enalapril

Question 22

which PPI decreases the anti platelet properties of clipidogrel?

Answer 22

omeprazole

Question 23

where does phase 1 metabolism occur?

Answer 23

hepatic circulation