Oral Absorption Flashcards
What are the two components of oral absorption?
- Dissolution
- Permeation
What is dissolution in the context of oral absorption?
All drugs must dissolve in the aqueous environment of the administration site for absorption to occur
What is permeation in the context of oral absorption?
All drugs must permeate across the lipid barriers (need to have some lipophillic character if permeating via passive diffusion)
Is disintegration ever a rate limiting step in oral absorption?
Never, it is either dissolution and permeation
How can dissolution be enhanced?
Ask patient to take drug with water
What PK factors are involved in Oral Absorption?
Ka (rate of absorption) and F (extent of absorption) are primary PK parameters that affect oral absorption
Cmax (rate alone), Tmax (rate and extent of absorption), and AUC (extent) are derived PK parameters
What are first-pass effects?
They are metabolic processes that eliminate drug before it can enter systemic circulation
What three factors is systemic drug absorption dependent on?
- Anatomical/physiological functions at absorption site
- Physicochemical properties of the drug
- Nature of drug product and dose size
What anatomical/physiological functions at the absorption site affect oral absorption?
- Nature of membrane
- Anatomic considerations
- Perfusion
- pH
What physicochemical properties affect oral absorption?
Solubility
Partition coefficient
What types of drugs can easily move across membranes?
Lipid soluble, unionized compounds, and smaller compounds will participate in passive diffusion
What are some important physiological characteristics of membranes in relation to drug absorption?
Permeability
Low surface tension due to protein adsorption (low surface tension allows drug to get closer to membrane)
Electrical properties due to distribution of ions
Are membrane proteins identically dispersed on a membrane’s apical and basal sides?
No, they are usually different. This difference in types of membrane proteins allows for vectoral transport (movement of substance in one direction)
What is the primary site of absorption?
Small intestine (especially duodenum and jejunum) due to large surface area
What is the benefit of agood blood supply in the GI tract in terms of drug absorption?
Drug absorbed is rapidly swept away from site of absorption. This maintains the concentration gradient and continued absorption of drug into GI blood supply
How does GI motility affect oral absorption?
In patients with faster motility may not allow the drug to remain within the absorption window for long enough period (limited extent of absorption)
If gastric emptying is slowed, gastric acid can break down drug
What are the effects of GI secretions on rate and extent of drug absorption?
- Mucous (drug needs to dissolve into mucous before absorbed across the membrane)
- Bile (emulsification of fats, good for lipid soluble drugs)
- Enzymes (breakdown of drug into inactive form)
- Ions (can complex with drug to form insoluble compounds and reduce absorption)
What is the most significant first-pass effect?
presystemic metabolism by enzymes in epithelial cells in GI tract and liver
This has a significant impact on bioavailability.
What is the advantage of drugs that can be absorbed into the lymphatic system?
Some lipophilic drugs can absorb right into the lymphatic system, completely bypassing many first-pass effects
What is the impact of pH on drug absorption?
Acidic drug in acidic environment will be unionized (best for absorption)
Basic drug in acid environment is ionized (not optimal for absorption)
Acidic drug in basic environment is ionized (not optimal for absorption)
Basic drug in basic environment is unionized (best for absorption)
What are the pH levels along the GI tract?
Stomach (1-2 when fasting, 3-4 when fed)
Duodenum (6-6.5)
Jejunum (7-8)
Colon (5.5 - 7)
What happens when drug enters the colon?
Large intestine has lower permeability and surface area
especially poor absorption of polar drugs
Absorption rate is so low that is becomes the rate-limiting step with controlled release dosage forms
Are absorption rates and extent of absorption independent of dissolution rate and extent of dissolution?
No, absorption is dependent on dissolution
Do larger doses mean a greater extent of absorption (as a percentage of the original dose)?
No, more drug in same volume of aqueous (limited by solubility)
What are saturable first-pass effects?
This occurs when drug dose is so high that all first-pass mechanisms are operating at full capacity, any added drug will not under go first-pass effects (increases F (bioavailability))
What is saturable active transport?
This occurs when in drugs that rely on active transport to cross membranes saturate transporters. Any additional drug is not going to increase rate of absorption (decreased F (bioavailability))
Review slide 20 for a summary of the steps involved in oral absorption
What is Ka (absorption rate constant)?
Ka indicates fraction of drug present at absorption site absorbed per unit of time
What is the link between absorption rate constant and rate of absorption?
Higher Ka (absorption rate constant) = faster absorption rate
What factors affect absorption rate constant?
- Ease of disintegration and dissolution of drug
- Gastric emptying rate and intestinal mobility
- Membrane transport
- Splanchic (GI tract) blood flow
What is the definition of rate of absorption?
Amount (or concentration) of drug absorbed per unit of time (impacted by size of dose)
Not the same as absorption rate constant (not impacted by size of dose)
Is tmax dependent on dose size?
No, it is dose independent
Tmax is dependent on Ka and k (elimination rate constant) instead
Is Cmax dependent on dose size?
Yes, but also Vd, F, Ka, k, Cls
Review slide 30 for effects of Ka and K on tmax, Cmax, and AUC
What is lag time in oral absorption?
This is the time delay seen prior to commencement of first-order absorption
What factors affect lag time in absorption?
- Delay in gastric emptying
- Formulation factors
What is bioavailability?
measurement of the extent of therapeutically active drug that reaches the systemic circulation
(fraction of dose of parent drug reaching systemic circulation)
Review slide 34 to review components of F (bioavailability)
What is the significant piece of information for Flip-Flop Kinetics?
In most lnCp vs. time curves, oral and IV terminal phases of their curves are parallel, therefore the represent k (elimination constant)
In drugs that exhibit flip-flop kinetics, the terminal curve is not parallel to IV elimination constant, indicating it actually represents Ka (absorption rate constant)
What are the two types of bioavailability?
- Absolute bioavailability
- Relative bioavailability
What is absolute bioavailability?
This involves a comparison of oral and IV administrations via AUC and dose in the same person on different occasions
review slide 36 for formula
What is relative bioavailability?
This involves comparison of the bioavailability of a drug in a patient vs. the reference bioavailability
review slide 36 for formula
What can be estimated from AUC?
Bioavailability
What technique is used to determine AUC?
Trapezoidal rule (review slides 39 and 40)
