Variability in drug metabolism

Question 1

What effect does grapefruit juice have on CYP3A4 enzymes?

Answer 1

Grapefruit juice inhibits the enzyme from metabolic processes -> higher levels of drug in blood -> more side effects

Question 2

Which functional groups are associated with toxicity?

Answer 2

Nitroaromatics
- metabolised to nitroso
Anilines (aromatic amines)
- metabolised to nitroso
Quinones (arene oxides)(epoxide of an arene)
- very reactive to nucleophiles
Alkyl halides 
- displaced as good leaving groups
Michael acceptors (ketone next to alkene double bond)
- very reactive
Carboxylic acids
- metabolised to acyl glucuronides

Question 3

Why are aromatic nitroso groups toxic? R-N=O

Answer 3

React with nucleophiles to form covalent adducts

- joins onto proteins and nucleic acids and affect function

Question 4

What is idiosyncratic drug toxicity blamed on?

Answer 4

Carboxylic acid groups

however there’s no absolute evidence that it is carboxylic acids that cause it

The theory is:
Mechanism believed to be formation of acyl glucuronides that are chemically stable and reach high plasma concentrations….
….then irreversibly transfer glucuronide to proteins and nucleic acids
Some evidence that increased plasma half life of acyl glucuronides = greater risk of IDT

Question 5

what is genetic polymorphism ?

Answer 5

Genetic polymorphisms are different forms of a DNA sequence. “Poly” means many, and “morph” means form. Polymorphisms are a type of genetic diversity within a population’s gene pool.

Question 6

What percentage of Caucasians and Chinese are poor metabolisers/ deficient in CYP2D6 ?

Answer 6

5-10% of Caucasians

1% of Chinese

Question 7

What percentage of of caucasians and East Asians are poor metabolisers for the CYP2C19 enzyme and what is the importance of this information ?

Answer 7

3-5% of Caucasians
15-20% of East Asians

it will impact the effect of the dosage

Question 8

why are there a number of drugs that have been associated with problems in drug discovery due to toxicity ?

Answer 8

potentially due to:
Metabolic activation to reactive intermediates
Interference with metabolic processes

Question 9

what are some potential clinical manifestations caused by drug toxicity due to functional groups ?

Answer 9

Cellular (hepatic) necrosis (animal toxicity)
Idiosyncratic toxicity (glutathione adducts, protein covalent binding, immunogenic response)
Drug-drug interactions (mechanism-dependent CYP inhibition)

Question 10

What is a bioisostere?

Answer 10

Isostere that has similar biological effects

Question 11

what do nitro bioisosteres do ?

Answer 11

Nitro bioisosteres mimic shape and/or electronic properties (nitro group is strongly electron withdrawing) of the nitro group.

Question 12

What do carboxylic acid bioisosteres do ?

Answer 12

Carboxylic acid bioisosteres that mimic shape and/or acidity of a carboxylic acid