Absorption
Passage of compound from the site of administration into the bloodstream, usually across a membrane.
Bioavailability
Generally refers to the rate and extent of absorption of intact drug. In this course, it refers to the fraction of an extravascularly administered dose that reaches the systemic circulation intact.
Relative Bioavailability
Comparison of the bioavailability between formulations or a drug given either by the same or different routes of administration.
• Situations: Oral tablet versus intramuscular solution; oral tablet versus oral capsule.
• Used when no intravenous formulation is available or when only comparative information is needed.
Bioequivalence
- Formulations containing the same dose of same chemical entity (in the same dosage form); intended to be interchangeable
- Situations of interest: clinical trials, generic sub.
- Considered to be therapeutically equivalent.
- A test preparation should differ by no more than some small degree (usually 20%) in exposure profile relative to a reference product
First-Pass Metabolism
Hepatic and Gut Wall Extraction
• 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.
Enterohepatic Cycling
Some drugs/metabolites are highly concentrated in the bile (polar, ionized, MW >300)
• 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
-Drug goes from liver → bile (stored in the gb). Gall bladder → intestine (until the gb is emptied, by effect of food). Intestine → portal circulation
•The drug has then completed a cycle known as the
enterohepatic cycle.
Describe the steps involved in the overall absorption process.
Drug at absorption site -> absorption -> drug in body -> elimination
Distinguish between perfusion and permeability rate limited absorption from solution.
- Perfusion Rate-Limitation: Small lipophilic molecules passing across most membranes, or very small hydrophilic ones readily passing through pores/channels between cells or membranes
• In such cases, 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
• Poorly permeable, with rate limitation lying with membrane • Insensitive to changes in blood flow
List 5 specific factors responsible for incomplete GI drug absorption.
- Lack of time
• For dissolution (of sparingly soluble drugs)
• For release (from some controlled-release products)
• For membrane permeation
-Particular problem for drugs given orally - Competing Reaction
• Instability (gastric pH); substrate for intestinal enzymes or microflora; complexation - Hepatic and Gut Wall Extraction
• 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.
Describe the effect of food on the concentration-time curve, following a single oral dose, when enterohepatic cycling is extensive.
Enterohepatic cycling can have a major impact on the plasma concentration-time profile. 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.
Explain why plasma or serum drug concentrations are used to measure drug concentration in the body rather than blood.
Less interference than whole blood. WB has a bunch of cells in it, which make it difficult for the machines to run assays compared to liquid-y texture of P/S (easier to manipulate).
Explain how the plasma concentration-time curve relates to pharmacologic activity.
Window of Therapeutics!
- First, have to have a high enough conc. to have an effect (minimum effective concentration)
- Concentrations need to stay in a ‘window’ for optimal effects
- Conc. can’t go beyond maximum tolerated conc. (toxicity/adverse effects)
- How long conc. stays above the MEC is the duration of action
- Lag in drug reaching MEC is the onset time
- Increasing conc. lead to increasing intensity
- Conc. never reaching MEC -> sub-therapeutic response
State the times when blood samples should be taken to assess bioavailability.
- Important to obtaining good information on the early exposure, peak exposure, peak time, and decline of the concentration-time curve after an extravascular dose
- 3 to 4 samples on the rising part of the curve and 2 to 3 points near the true peak time are needed
Describe the determinants of the ratio of drug concentrations in blood and plasma, and be able to calculate the ratio or the other determining factors.
Serum and plasma conc. almost always identical
- One exception: serum doesn’t have CF -> so, if a drug binds to CF, conc. will differ
- Drug bound to CF will be removed, so higher conc. in plasma and lower conc. in serum
PK analysis is usually performed with blood. Why?
- Blood is a more direct measurement than urine
- Drug distributes more readily in blood
- Drug is eliminated from body mainly by blood
- Blood reaches more parts of the body
- PK parameters are based on drug characteristics in blood
What is k?
- Rate constant of elimination of a process
- Units are expressed in per unit time
- Amount of time it takes for concentration of drug in the body to drop by half
- By default, k (without a subscript) is the elimination rate constant
Window of Therapeutic Concentration
- Assume that a certain window of plasma concentrations will give the optimal therapeutic response.
- When the concentration is too high there is a high probability of adverse events.
- When the concentration is too low there is an unacceptably high probability of a subtherapeutic response.
- The concentrations between the two are referred to as the therapeutic concentration window.
Whole Blood Compared to Plasma+Serum
- If drug can’t get into blood cells, then there is a lower conc. in WB due to a greater volume
- If drug can move freely, then conc. will be the same in each
- Cb/C high = same conc. / low = higher conc. in plasma
- How to keep it in Plasma? Could have it where drug can’t penetrate blood cells, but also not have any free drug floating around (when high % is bound, nothing to go into to begin with)
Name: Cb, C, H, fu, p, fu*p.
- Cb: drug conc. in whole blood
- C: drug conc. in plasma (unbound and bound)
- H: hematocrit (assume 0.45) or (V rbc / total blood V)
- fu: fraction unbound = ( Cu / C )
- p: partition coefficient = ( Cbc / Cu )
- fu*p: [drug]bc/[drug]plasma
