drug metabolism pathways

Question 1

what are drug metabolism reactions?

Answer 1

	Wide range of metabolic reactions 
	 C oxidation dominates
	hydroxylation
	oxidative cleavage
	Existence of sequential and parallel pathways – need to be able to differentiate between these two possible pathways

Question 2

what is sequential metabolism?

Answer 2

1. phase II conjugation

2. further phase I reactions

Question 3

what are further phase I reactions/

Answer 3

 Sequential oxidation on the same C
 CH2OH -COOH
 Sequential oxidation on a different C
 e.g., hydroxylation of a demethylated metabolite

Question 4

how can you predict routes of drug metabolism?

Answer 4

 Look at the chemical structure – need a chemical stricture in order to have an idea
 Are there key functional groups? identify the groups when you know what there expecations are
 Direct phase II metabolism – OH, NH2 or COOH (easiest ones to identify as you know it can have a Direct phase II reaction)
 Are there other vulnerable groups?
 Esters (hydrolysis), nitro (reduction), O-methyl (oxidative cleavage and removal of the methyl group)
 Is there N or O? Oxidative cleavage
 Are there any other C sites vulnerable to oxidation?
 Benzene ring – aromatic hydroxylation
 Try and eliminate what it cant be and then work out from there what it you may be able to say it is

Question 5

what are the preferred reactions?

Answer 5

1. Reactive  - Cs – these carbons are adjacent to either a oxygen or a nitrogen connected to a c=c. this means they can very easily accept a hydroxy group.
2. Side chain hydroxylations
3. Aromatic hydroxylations

Question 6

how can you identify metabolites?

Answer 6

• products excreted in urine so you can take samples
• product circulate in plasma
• products fomed in incubations in liver tissue
• complete recovery is rare

Question 7

what is antipyrine metabolism?

Answer 7

four projected sites of oxidations. two oxidations on the aromatic ring is major site.

• amino metabolite where you remove methyl group from nitrogen
• alcoholic metabolite - oxidation of alpha carbon
• phenolic reactions - oxidation of ring

Question 8

summary of antipryine metabolism/

Answer 8

 3 parallel pathways
 Incomplete recovery of the dose
 4th metabolite (aromatic –OH) unstable – not usually seen

Question 9

what is propranol metabolism?

Answer 9

 b blocker – side chain with an amine
 4 important sites of metabolism - hydroxy group can undergo direct conjugation. Two alpha carbons on each side of the carbon – removal of methyl group or whole side chain.
 3 sites for oxidation

Question 10

what is a summary of proproanolol metabolism?

Answer 10

• 3 parallel phase I metabolic pathways – 3 primary metabolites
• Aromatic OH Met II
• Dealkylation – initial -C Met III
• Deamination – initial -C Met IV
• Sequential metabolism:
• Secondary metabolites – Met V and VI
• In total - 5 phase I metabolites + direct phase II

Question 11

what is lignocaine metabolism?

Answer 11

amide with the green arrow – potential hydrolysis on this location.
Two ethyl groups attached to the nitrogen n dealkylation but you are unsure which one it would occur (2 possible places it could occur).
Aromatic hydroxylation in para position so this is the most sensitive

Question 12

what is the mechanims of lignocaine metabolism?

Answer 12

2- metabolite formed by removing ethyl group
3- metabolite further to remove another ethyl group
2 and 3 are the major circulating metabolites in the plasma.
4- formed via two sites, direct hydrolysis from parent molecule or form it by the hydrolysis of metabolite 3 (sequential).
4&5 are the two major metabolites in the urine.
This tells us that the most likely scheme of metabolism is produce 2 and 3 which are placed in the plasma and then you produce the terminal metabolites 4 and. 5 which are excreted within in the urine. You cannot rule out that metabolite 4 would be produced straight from the parent molecule but it is mainly going to be produced from the 2 and 3 metabolites.

Question 13

what is the summary of lignocaine metabolism?

Answer 13

Analysis of metabolites in plasma and urine indicates:
 2 parallel pathways Met II and IV
 Sequential metabolism Met III and V
 Crossover between pathways giving common end products excreted in urine Met V

Question 14

what is imipramine metabolism?

Answer 14

4 (5) sites of oxidation
complex metabolic scheme. Tri-cyclic ring with side chain on the bottom. Number of alpha carbons. Positions of the N demethylation has 2 poisitons and then also aromatic dihydroxylation.

Question 15

what is the mechanism of imipramine metabolism?

Answer 15

• Primary metabolites are the green colours 2,3 and 4. Formed from parent molecules.
• From metabolite 2 you can have a number of sequential metabolic reactions.
• Metabolites 5, 6 and 7 are secondary metabolites.
• 5- secondary metabolites with addition to hydroxylation you have another n-demethylation
• 6- two sequential n-demethylation that occur from tertiary amine to a primary amine
• 7 – aromatic hydroxylation of number.4 and then n-demethylation that occurs
• 10,11 and 12 you completely lose your side chain
• 11 = quite specific, metabolite is shown as a primary metabolite. This is bevause you could have the metabolite as it can be formed directly from the parent molecule if you lose the side chain. The bracket suggests it can be formed from either metabolite 3 or 6 through sequential metabolism
• 10 and 12 are the products are sequential metabolites from either of the sequences

Question 16

what os the summary of imipramine metabolism?

Answer 16

 4 parallel pathways – primary Met II, III, IV and XI
 Sequential metabolism
 Secondary Met V, VI, VII, X and XII
 Tertiary Met VIII, IX (X and XII)
 Crossover between pathways giving common end products
 Met V, VII, VIII, IX, X and XII