Drug Metabolism: Phase I and II

Question 1

Drug Metabolism

Answer 1

is the enzymatic conversion of the drug to another chemical entity. Liver is most important drug-metabolising organ; kidney, gut mucosa, lungs and skin also contribute. Metabolism in the liver reduces the bioavailability of the drugs when administered by the enteral (oral) route. Occurs in 2 phases.

Question 2

Bioavailability

Answer 2

amount of drug that is available for systemic circulation - ready to work. Determined by the metabolism of the drug.

Question 3

Hepatic drug-metabolising enzymes (microsomal enzymes)

Answer 3

are embedded in the smooth endoplasmic reticulum of the liver hepatocytes.

Question 4

Non-polar molecules

Answer 4

cross the plasma membrane to be metabolised more readily polar molecules - non-polar and lipophilic drugs can cross membranes more easily in contrast to hydrophilic drugs.

Question 5

Phase I Reactions

Answer 5

Change in the drug by oxidation, reduction, or hydrolysis. Usually forms chemically reactive metabolites that can be pharmacologically active and/or toxic

Question 6

Phase I Oxidation

Answer 6

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.
Can produce harmful metabolites

Question 7

Phase I hydrolytic reactions

Answer 7

ester and amide bonds are susceptible to hydrolysis

Question 8

Liver P450 Systems

Answer 8

Cytochrome P450 enzymes are haem proteins which comprise a large superfamily. P450 activity is genetically determined: some persons lack such activity leading to a higher drug plasma level (adverse reaction);some have high levels that leads to a lower plasma level (and reduced drug action). Other drugs can interact with P450 systems and either induce activity (tolerance, pharmacokinetic antagonism).

Question 9

Phase II Reactions

Answer 9

involve combination of the drug with one of several polar molecules to form a water-soluble metabolite. Conjugation usually involves the reactive group produced by Phase I. Usually terminates all biological activity. Conjugated produces can be excreted via the kidney. Some drugs can go directly to phase II metabolism (and also have metabolites that are pharmacologically active).