DSA - Biotransformation, Pharmacogenomics, Clinical Trials

Question 1

What is biotransformation?

Answer 1

The enzymatically-driven process whereby a substance is changed from one chemical to another by a chemical reaction within an organism

Question 2

What is a xenobiotic?

Answer 2

Foreign substance within a body

Question 3

What are the properties a xenobiotic must have in order to be excreted by the kidneys?

Answer 3

Polar compounds

or compounds with small molecular volumes

Question 4

What are the properties of compounds that undergo biotransformation?

Answer 4

Lipophilic

Unionized

Large compounds

Biotransformation results in the termination of their actions and facilitate elimination

Question 5

What is the body’s general strategy when it comes to biotransformation?

Answer 5

Elimination of xenobiotic compounds into more polar (and sometimes larger) derivatives

Question 6

How does biotransformation affect the activity of compounds?

Answer 6

Biotransformation reactions may lead to a product that is still biologically active or even one that is more active than the parent compound

Activation

• L-dopa –> dopamine
• In this case L-dopa is a prodrug

Active compound –> Active compound
- Diazepam –> oxazepam

Inactivation
- Acetylsalicylic acid (aspirin) –> acetic acid + salicylate

Question 7

What is a prodrug?

Answer 7

An inactive drug that undergoes biotransformation to become an active drug

Some drugs are designed such that they have an added functional group attached that makes the drug inactive until it is absorbed and the protective functional group is removed by an enzyme involved in biotransformation.

Question 8

What is the First Pass effect?

Answer 8

The process by which oral drugs are absorbed in the small intestine and transported to the liver via the hepatic portal system, where they undergo extensive metabolism

• Drugs given via parenteral routes of administration DO NOT undergo first pass biotransformation

First pass effect greatly limits the bioavailability of some drugs so much so that alternative routers of administration must be explored

Some drugs may be metabolically inactivated or activated (less common) in the stomach (due to acidity) and GI tract (digestive enzymes and intestinal bacteria)

• Normal GI flora can increase the bioavailability of certain drugs, such as estrogens used in contraception, by increasing enterhepatic cycling of metabolites
• Antimicrobial drugs may reduce estrogen efficacy

A classic example of a drug that undergoes extensive first-pass biotransformation is morphine

• The bioavailability of oral preparations of morphine is roughly 25% and parenteral administration is preferred