2 - Drug Absorption & Bioavailability Flashcards
What is bioavailability?
Fraction of the drug that reaches the systemic circulation unchanged
Where is the majority of a drug absorbed?
Small intestine
Are drugs absorbed substantially in the stomach? Why or why not?
- No
- Acidic drugs are unionized in the stomach, but aren’t absorbed b/c thick mucous layer and thick gastric wall
Function of P-glycoprotein
Pump that pushes substances foreign to the body back into the GI lumen and prevents its absorption
How do you calculate absolute bioavailability?
F = (AUC po / dose po) / (AUC IV / dose IV)
How do you calculate relative bioavailability?
F = (AUC / dose for new formulation) / (AUC / dose for standard formulation)
What is bioequivalence?
- Comparing relative bioavailability of the brand vs. generic drug
- No more than 20% difference between AUC’s and Cmax’s
- Mean ratio of the AUC and its respective 90% confidence interval should lie w/in the limits of 0.8 to 1.25; 1.0 = identical (Cmax should also lie w/in 0.8 to 1.25 but not its 90% confidence interval)
What is bioequivalence for critical dose drugs?
- 90% confidence interval on the AUC ratio should lie w/in 0.9 to 1.12
- 90% confidence interval on the Cmax ratio should lie w/in 0.8 to 1.25
What are some important factors governing the absorption of drugs?
- Molecular size and shape of drug and its concentration
- Lipid solubility of unionized form of the drug
- Chemical or physical interactions w/ other drugs or food
- Characteristics of the dosage form (disintegration and dissolution)
- Fluid volume in GI tract
- Osmolality of intestinal contents
Location of P-glycoprotein
Apical surface of epithelial cells in liver, kidney, brain capillaries, placenta, and GI tract
Is p-glycoprotein an example of passive or active transport?
- ATP dependent, so active transport
- Able to pump against a concentration gradient
Describe the drug interaction between dabigitran and verapamil
- If verapamil given 1h prior to dabigitran, bioavailability of dabigitran will increase dramatically b/c verapamil is P-gp inhibitor
- If dabigitran given 2h prior to verapamil, no interaction
What does it mean when a drug is a P-gp inducer?
Absorption of other drugs will be decreased b/c P-gp will be preventing absorption
What does it mean when a drug is a P-gp inhibitor?
Absorption of other drugs will be increased b/c P-gp isn’t preventing the absorption
Describe the drug interaction between dabigitran and rifampin
Rifampin is a strong P-gp inducer, so decreases absorption of dabigitran
Describe the drug interaction between digoxin and amiodarone
Amiodarone = P-gP inhibitor, so absorption of digoxin increases by 100%
Describe the drug interaction between digoxin and rifampin
Rifampin = P-gP inducer, so decreases digoxin absorption by 30%
How can you assess whether patients have adequate GI function?
- Presence/ absence of bowel sounds
- Absence of diarrhea, nausea, or constipation
- Tolerance of diet or tube feedings
How can you assess if the stomach is emptying and nutrients and drugs are being absorbed?
- Acetaminophen absorption testing
- Not absorbed in the stomach but completely absorbed in the small intestine
Is acetaminophen affected by CYP 3A4 or P-gP?
No
What is the method of administration for acetaminophen absorption testing?
- Administer 650 mg of acetaminophen (975 or 1000 mg in pt over 90 kg) ideally as liquid product
- Measure plasma levels at 0.5, 1, and 2 hours after dose
- Determine AUC
- Compared this value w/ a weight-adjusted value for healthy volunteers
What are some limitations to the acetaminophen absorption testing?
- Ensure no acetaminophen has been received for at least previous 12 h
- Severe liver dysfunction may prolong t1/2
- Assume Vd is fixed at 0.95 L/kg
- Can’t be assessed in the presence of lipemic serum
- Hyperbilirubinemia can cause false positives for acetaminophen
