Absorption (Systemic)
- Passage of compound from the site of administration into bloodstream (usually across a membrane)
- Drug at absorption site -> absorption -> drug in body -> elimination
Extravascular Administration
Refers to any route other than directly into the bloodstream (intravascular)
Bioavailability
Refers to the rate and extent of absorption of intact drug; refers to the fraction of an extravascularly administered dose that reaches the systemic circulation intact
Absolute Bioavailability
Based on the ratio of plasma (AUC) or urine (Ae(∞)) of an extravascular dose (ev) to an intravenous dose (iv)
Relative Bioavailability
- Comparison of the bioavailability between formulations or a drug given either by the same or different routes of administration (i.e. oral tablet vs. intramuscular solution)
- Used when no intravenous formulation is available or when only comparative information is needed
Bioequivalence
- Formulations containing the same dose of same chemical entity, generally in the same dosage form, intended to be interchangeable
- (i.e. clinical trials or generic substitution)
- Bioequivalent preparations are considered to be therapeutically equivalent
- To be bioequivalent, a test preparation should differ by no more than some small degree (usually 20%) in exposure profile
Perfusion (BF) Rate Limitation
- Small lipophilic molecules (many drugs) passing across most membranes, or very small hydrophilic ones readily passing through pores/channels between cells or some membranes
- The membrane offers no effective barrier to drug molecule, and absorption rate varies with rate of blood flow
Membrane Permeability Rate Limitation
- Seen with polar hydrophilic compounds moving across many membranes, e.g., intestinal tract
- Poorly permeable, with rate limitation lying with membrane
- Insensitive to changes in blood flow
Gastric Emptying
-All drugs in solution are absorbed faster from intestine than stomach, irrespective of pH
• Any factor affecting the rate of gastric emptying may influence the systemic kinetics of the drug when given orally either in solution or in a solid dosage form
INCOMPLETE ABSORPTION
-Lack of time: for dissolution (of sparingly soluble drugs), for release (from some controlled-release products), for membrane permeation (e.g., polar drugs)
• particular problem for drugs given orally
-Competing Reaction: instability (gastric pH); substrate for intestinal enzymes or microflora; complexation
–Hepatic and Gut Wall Extraction (more detail in other card)
ENTEROHEPATIC CYCLING
- Some drugs are highly concentrated in the bile
- Due to active transport from the sinusoids of the liver to the bile canaliculi across the hepatocyte
- For a drug to be highly secreted into the bile it must be a substrate for the secretory mechanism
- Glucuronides that are polar/ionized/high MW(over300) are highly excreted into the bile
- CYCLE: Drug goes from liver to bile (stored in gb), gallbladder to intestine (until gb is emptied by effect of food), intestine to portal circulation
If administered compound is a prodrug…
(without activity), bioavailability is frequently based on measurement of active metabolite, in which case the intravenous reference is the active metabolite
Rate Limiting Steps in Absorption
- Absorption of drug from in a solution: Movement through membranes (lipid bilayers)
- Transcellular permeation either by passive diffusion, active transport or passive facilitated transport.
- Paracellular transport is always passive.
Drug Release from Solid Formulations
solid drug -> release -> drug in solution -> entry into body -> absorbed drug
Enterhepatic Cycling can have major impact on plasma concentration time-profile…
(EX.) This drug clearly shows slow release from the intact tablet and shows enterohepatic cycling as evidenced from the second peak in the concentration-time profile when food is taken 2 hours after the tablet
Hepatic and Gut Wall Extraction
- under incomplete absorption (for GI tract)
- low bioavailability occurs for drugs that, when given orally, exhibit a high hepatic extraction ratio or are extensively metabolized in the gut wall. This is called the First-Pass Effect.
