Question

Most drugs cannot be excreted unchanged by the body but have to go through the process of drug metabolism. Drug metabolism enables structural change within the drug allowing for its’ elimination from the body. Describe in detail the processes involved in drug metabolism. Your answer should include the reactions of phase I and phase II metabolism, the control of expression of cytochrome P450s and detailed examples of these processes in drugs chosen by you.

Answer 1

Drug metabolism- Whenever a drug is administered through the oral route, it goes through the hepatic first pass route to the liver, where the drug metabolism occurs. More technically, it is the modification of the parent drug compound in the liver of the organism to make it either more active or less active. These modifications are done by special enzyme systems present in the liver.

Results of Drug metabolism-

a. Some drugs can get inactivated (conversion to inactivated metabolite) (examples- Chloramphenicol)

b. Some drugs can get activated (conversion to activated metabolite)(example- Levodopa)

c. Some active drugs can get transformed to activated metabolite

Phases of drug metabolism- There are 2 phases of drug metabolism which includes- Phase I and Phase II

PHASE I drug metabolism---

· The phase I of the drug metabolism is characterised by addition of various functional groups (OH, COOH, NH2)to the drug or such modifications that make the drug suitable for its uisage.

· This modifications includes- Oxidation, Reduction, Hydrolytic reactions.

· Oxidation- involves the addition of O atom or negatively charged radical or the substraction of H atom or +vely charged free radicals.

· The main enzyme system that is involved is- Mono oxygenases, which are Present in the liver.

· One of these monooxygenases is the Cytochrome P450(which is a microsomal mixed function oxidase)

· However other non-microsomal enzymes can also be involved in the oxidation, eg- alcohol dehydrogenase, aldehyde dehydrogenase and monoamine oxidase.

· The various oxidative reactions are—N-dealkylation, O-dealkylation, Aliphatic hydroxylation, aromatic hydroxylation, N-S oxidationoxidation,

· Reduction involves the addition of hydrogen in the drug .

· The various substrates that undergo reduction reactions are- Azo, nitro compounds, halogenated hydrocarbons.

· The reduction of the azo and nitrocompounds is undertaken by the cytochrome P450

· Other enzymes of reduction are- aldehyde reductase, aldose reductase,etc.

· Hydrolysis involves the cleavage of the drug molecule by utilizung a molecule of water.

· Substrates for hydrolysis reactions include ethers, esters, amides.

Phase II drug metabolism-

        This phase is involved in the addition to charged groups to the already metabolised drug substances in phase I. The various groups that are added are Glutathione, sulphate, etc.

The various reactions that occur in phase II of the drug metabolism are-

· Methylation(catalysed by-Methyl transferases)

· Sulfation (catalysed by- Sulfotransferases)

· Acetylation ((catalysed by-N acetyltransferases)

· Glucuronidation

· Glutathione conjugation(catalysed by- Glutathione S transferases)

· Glycine conjugation (catalysed by- Glycine N acyltransferase)