Absorption and Distribution

Question 1

Describe how drugs are absorbed and passive diffusion.

Answer 1

Oral drug absorption

• Drug in intestine is absorbed into portal circulation via portal vein.
• Portal blood is first delivered to liver.
• Liver is the major organ of biotransformation.

Passive diffusion through membranes
- When the membrane is narrow and/or the permeability, surface area or extracellular concentration are high then flux across membrane is favoured

Question 2

Describe the transporters that increase or decrease intestinal absorption.

Answer 2

SLC Influx Transporters

• INCREASE intestinal uptake of drugs
• Anion and Cation membrane transport

ABC Eflux Transporters

• DECREASE intestinal uptake of drugs
• P-glycoprotein

Question 3

How do the acid/base properties of drugs control ionisation and entry to cells?

Answer 3

Role of Drug Ionization

• Ionization influences drug movement between aqueous and lipid environments
• Strong acids/bases - ionized at any pH (very few drugs)
• Weak acids/bases - extent of ionization depends on the pH of the aqueous environment
• For a weakly acidic drug an increase in H+ (a decrease in pH) suppresses ionisation and favours diffusion through a membrane

Question 4

Describe how the route of administration can influence the amount of drug available in the body (systemic availability).

Answer 4

If a drug reaches the tissues without travelling through the intestine and liver first then it may reach tissues and produce its pharmacological effect before it is metabolised.

• Intravenous injections
• Eye drops and nasal drops
• Dermal delivery
• Sublingual tablets
• Rectal administration

Question 5

What amount of drug crosses cell membranes, is metabolised and eliminated?

Answer 5

The free fraction of drug

• A newly absorbed drug enters the portal circulation
• Plasma proteins may limit the free drug concentration
• Only unbound drug in plasma can enter tissues, ie total drug in serum is not available
• Serum albumin binds many acidic drugs
• a1-acidglycoprotein (AAG) binds many basic drugs

Question 6

What is the first step in elimination for most drugs?

Answer 6

Phase I Metabolism by CYPs

Question 7

Define Phase I Reactions

Answer 7

Phase 1 reactions

• Chemical conversion of a lipophilic chemical into a more polar analogue
• Inclusion of new functional group, usually by oxidation, reduction or hydrolysis.
• Decreases lipophilicity

Question 8

Define Cytochromes P450

Answer 8

Cytochromes P450 (CYPs)

• The major class of phase I biotransformation enzymes
• Unlike most enzymes CYPs act on diverse substrates, including the drugs and endobiotics to which we are exposed (Low substrate specificity)

Question 9

How do Cytochromes work?

Answer 9

Structure and Function

• Have haem group involved in oxygen activation
• The polypeptide chain differs between CYPs and controls substrate specificity
• Each CYP is encoded by a different gene
• Variations in amino acid sequence often influence enzyme function (Pharmacogenomics)