Unit 2 - Oral absorption 2

Question 1

What effect can grapefruit juice have on permeation?

Answer 1

A single glass of grapefruit juice is enough to alter the oral bioavailability of some drugs
If the juice is drunk over several days the effects are long lasting
- separating the dose of medicine and the ingestion of grapefruit juice does not prevent the interaction

Question 2

How does grapefruit juice affect permeation of mediations?

Answer 2

Inhibition of P-glycoprotein

Inhibition of intestinal CYP3A4

Question 3

How does expression of P-glycoprotein change in the small intestine?

Answer 3

Greatest in more distal regions of small intestine

- higher P-glycoproteins levels in ileum > jejunum

Question 4

What type of molecules are substrates for P-glycoproteins?

Answer 4

Hydrophobic molecules
Amphipathic molecules
Cationic molecules

Question 5

Which CYP450 enzyme is expressed in enterocytes?

Answer 5

CYP3A4

Question 6

Which drugs are P-glycoprotein inhibitors?

Answer 6

Erythromycin
Cyclosporin
Ketoconazole
Quinadine
Ritonavir

Question 7

Which drugs are P-glycoprotein inducers?

Answer 7

Rifampin

St. John’s wort

Question 8

How do statins work?

Answer 8

Competitively inhibit HMG-CoA reductase

- first committed enzyme in the biosynthesis of cholesterol

Question 9

What are the effects of statins?

Answer 9

Decreased synthesis of cholesterol by the liver
- reduction in synthesis and secretion of lipoproteins from the liver
- up-regulation of hepatocyte LDL receptors and increased removal of apoE- and apo-B containing lipoproteins from circulation
Net effect
- lower plasma concentration of cholesterol-carrying lipoproteins

Question 10

What is a common adverse effect of statins?

Answer 10

Statin-induced myotoxicity

- 10% - 30% of patients

Question 11

What are the symptoms of statin-induced myotoxicity?

Answer 11

Apoptosis
Proteolysis
Muscle remodelling
Fatigue
Cramps
Myalgia

Question 12

When might high concentrations of statins occur in the myocyte?

Answer 12

Pharmacokinetics of a statin is altered

• activity of liver influx membrane transporters
• OATPs
• statin metabolism

Question 13

How does hepatocellular uptake affect pharmacokinetic and pharmacodynamic parameters of statins?

Answer 13

Uptake into liver withdraws statins from portal venous blood
- decreases plasma concentrations
- decreases risk of myotoxic damage
Risk of occurrence of myopathy increases with statin plasma concentration

Uptake is a prerequisite for inhibition of 3-hydroxy3methylglutaryl-coenzyme A reductase (HMG-CoA) in hepatocytes
- necessary for desired lipid lowering effect

Question 14

What effect does inhibition of hepatocellular uptake of statins have?

Answer 14

Increase the risk of myotoxic side effects

Impair the therapeutic efficacy of statin therapy

Question 15

Which transporter are statins a substrate for?

Answer 15

OATPs

• OATP 1B1
• OATP 1B3
• OATP 2B1

Question 16

Give some examples of hydrophilic statins

Answer 16

Rosuvastatin

Pravastatin

Question 17

How do hydrophilic statins enter hepatocytes?

Answer 17

Poor membrane permeability and not significantly metabolised
Transporters are important in PK and PD
Access to target cell
- hepatocyte via SLC carrier
- OATP1B1 important for hepatic uptake
Molecule’s hydrophilic character associated with unwanted side effects at other tissues
- muscle

Question 18

Give some examples of lipophilic statins

Answer 18

Simvastatin

Lovastatin

Question 19

How do lipophilic statins enter hepatocytes?

Answer 19

Show good membrane permeability and significantly metabolism
- CYP450
Pharmacokinetics and pharmacodynamics less determined by drug transporters
Access to target cell
- hepatocyte via SLC carrier OATP 1B1 less important
Molecule’s hydrophobic character means more ready uptake into other tissues
- muscle

Question 20

What effect does cyclosporine have on co-administration with pravastatin or rosuvastatin?

Answer 20

Cyclosporine is a potent inhibitor of OATP 1B1

• substantially increases extent of oral bioavailability
• pravastatin (x5 - x12 fold increases in AUC)
• rosuvastatin (x7 fold increases in AUC)

Question 21

what would be the solubility and permeability of drugs polar in nature

Answer 21

Drugs polar in nature would be the ones that are high in solubility, low in permeability

Question 22

Give an example of an acid labile drug (a drug that is easily destroyed in acidic environment)

Answer 22

• acid- labile - Phenoxymethylpenicillin (penicillin V/VK) to be taken on an empty stomach because exposure to acid with prolonged gastric residence leads to chemical degradation and reduced bioavailability with risk of therapeutic failure

Question 23

Give an example of a drug that is soluble in bile/fat

Answer 23

• Fat-/bile enhanced dissolution of poorly soluble drugs eg. Saquinavir to be taken with meals because the bile acids released assist solubilisation and enhance drug dissolution. High fat meals also can enhance extent of absorption eg. Saquinavir bioavailability doubles with a high fat cooked breakfast !

Question 24

Give examples of drug, food chelation

Answer 24

• Chelation - eg. bisphosphonates to be taken on an empty stomach because calcium and other cations in food can form insoluble chelates.

Similarly, fluoroquinolones form slightly soluble complexes with metal ions of food showing reduced bioavailability.
Casein and calcium present in milk decrease the absorption of ciprofloxacin.

Tetracycline taken one hour before or two hours after meals, and not taken with milk because it binds calcium and iron forming insoluble chelates, and influencing its bioavailability. Even a little quantity of milk containing extremely small amounts of calcium severely impair the absorption of the drug (coffee, tea)