1 - Drug absorption and Bioavailability Flashcards
Describe the oral absorption process
- a drug given orally may have only a fraction of the dose reaching the systemic circulation
- this fraction is known as bioavailability
- drug must cross a number of biological membranes before entering the blood stream
What is a barrier to oral absorption, ie why is it not 100% like IV?
- has to cross lots of membranes before entering systemic circulation (blood stream)
- during the absorption phase, the drug molecules will encounter enzymes (ex: CYP 3A4) that metabolize the drug OR even pumps that push the drug back into the GI lumen and prevent its absorption (ex: P-gp)
Define bioavailability
A term used to define the rate and extent to which a drug (in a particular dosage form) enters the systemic circulation intact.
Describe factors that can influence bioavailability
Drugs tend to undergo some form of ‘biotransformation’ by enzymes within the intestinal epithelium and liver, which can substantially reduce the amnt off ‘unchanged’ drug that actually enters the systemic circulation after oral admin. => We want to know how much of the oral drug actually makes it into systemic circulation.
- This is known as the ‘first-pass’ effect and is significant for a number of drugs
Describe the oral drug absorption profile
The time that it takes to be absorbed AND the peak it reaches are dependent on both the absorption AND elimination half-lives.
Bioequivalence
for oral drugs this is determined by comparing the relative bioavailability of the Brand vs. the Generic named drug.
- there must be no more than a 20% difference between the AUC’s and Cmax’s
How do we achieve the bioequivalence standard of no more than 20% difference?
- the mean ratio of the AUC AND its respective 90% confidence interval should lie within the limits of 0.8 to 1.25 (with 1.0 being identical bioavailability).
- the Cmax ratio should also lie within 0.8 to 1.25 (but not its 90% confidence interval)
Describe bioequivalence for critical dose drugs
bioav. of generics shouldn’t vary much from the trade product.
- The 90% confidence interval (C.I.) on the AUC ratio should lie within tighter limits of 0.9 to 1.12
- the 90% C.I. .on the Cmax ratio now needs to lie within the 0.8 to 1.25 limit.
List the critical dose drugs
cyclosporin, digoxin, flecainide, lithium, phenytoin, sirolimus, tacrolimus, theophylline, and warfarin
What is the acceptable bioequivalence ratio limits for standard drugs? (AUC, Cmax)
- AUC ratio limits: 0.8 - 1.25
=> it’s C.I should also lie within this range - Cmax ratio limits: 0.8 - 1.25
=> for a standard drug, we don’t need to worry
about the 90% C.I lying within this range
What is the acceptable bioequivalence ratio limits for CRITICAL dose drugs?
- AUC limits: 0.9 - 1.12 ; same with C.I
- Cmax limits: 0.8 - 1.25 ; same with it’s C.I.
Where is P-gp located?
Located on the apical surface of endothelial cells: liver, kidney, brain capillaries, placenta, GI tract.
=> controls drug movement.
Describe DI’s that involve the P-gp
some drugs can be inhibitors or inducers of P-gp, will affect how much drug is absorbed/delivered to the system.
P-gp: active or passive transport?
Uses ATP, thus is able to pump a drug against the concentration gradient
P-gp in the GI tract has been known to limit the bioavailability of what drugs?
digoxin, paclitaxel, cyclosporine, dabigatran, and HIV protease inhibitors
