F8. Absorption from GI tract2 Flashcards
Describe colonic bacteria
Colonic bacteria are predominantly anaerobic and secrete enzymes that are capable of metabolizing endogenous and exogenous substances (carbohydrates, proteins) which escape digestion in the upper GI tract
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what is the primary function of the colon?
The primary function of the colon is absorption water and electrolytes, therefore the amount of fluids is relatively low, especially in distal colon
How does size compare between the colon and small intestine?
The large intestine is wider and shorter than the small intestine (~125cm)
microvilli in small intestine vs colon?
-Although microvilli are present, mucosa of the large intestine has no villi
-There are irregular folds known as plicae semilunares which are along with microvilli increase the surface area 10-15 times relative to a cylinder
-Therefore, surface area available for absorption in colon is much lower that in small intestine but still higher than in stomach
gut wall metabolism in the colon vs small intestine?
-Gut wall metabolism: the spectrum of metabolising enzymes (Phase I and Phase II) are similar in small intestine and colon
-However, since the surface area in the colon is lower, the total metabolic activity of the colon is also lower
Drug absorption in the colon vs small intestine?
-Drugs absorbed from the colon and upper rectum are absorbed into portal vein and therefore are subjected for hepatic first-pass metabolism
-Drugs absorbed from the lower rectum and anal canal are not getting into portal vein and therefore avoid hepatic first-pass metabolism
transporters in the colon vs small intestine?
-Unlike the small intestine, there are no documented active influx transporters, so carrier-mediated absorption is practically absent
-On the other hand, efflux transporters (such as P-glycoprotein) are expressed at a higher density in the colon versus small intestine
-Despite all the above “negative” information, long residency time and low enzymatic activity in the colon results in significant absorption from colon for some drugs.
Describe extravascular administration
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Plasma concentration-time profile after oral administration?
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How to find C max, Tmax and Half-life on a graph?
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Finding half-life and elimination rate constant?
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Describe kinetics of oral absorption
-In most cases, the oral absorption of drugs (as well as absorption after other extravascular administrations) approximates first-order kinetics
-In first-order kinetics the rate of absorption is proportional to the amount remaining to be absorbed
-Sometimes a drug is absorbed at essentially a constant rate. In this case the rate of absorption is not dependent on the amount remaining to be absorbed
Describe first order kinetics
-The rate of emptying will decrease because it depends on the amount of the drug remaining in the intestinal lumen.
-The rate of emptying (g/min) declines exponentially with time and is proportional to the amount of the drug remaining in the lumen (g) and the efficiency of the absorption (diffusion, permeability)
-The rate of emptying relative to the amount of the drug remaining in the lumen will remain constant (Ka, absorption rate constant).
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First order oral absorption kinetics calculations
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Method of residuals?
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Finding absorption half-life and Ka from graph?
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Calculating AUC
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Relationship between absorption and elimination
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How to calculate CL and Vd from extravascular administration?
-We cannot calculate CL and Vd from extravascular administration UNLESS we know absolute bioavailability
-In order to know absolute bioavailability, as you will see in a few slides, we need to administer the drug intravenously
-If we administer the drug intravenously, then we can calculate CL and Vd from that intravenous administration
-In other words – in most cases it is not practical to calculate CL and Vd from extravascular administration, as knowledge of F is needed
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What is absolute bioavailibility
-Fraction of administered dose reaching the systemic circulation in unchanged form
what are the two major aspects of absolute bioavailability
-Rate and extent of absorption across the GI wall
-Extent of drug metabolism or breakdown before it reaches the systemic circulation
The oral bioavailability (F) is commonly less than 1 (less than 100%), why?
-Loss in the faeces (not absorbed or effluxed by P-glycoprotein)
-Decomposition in the lumen
-Destruction within the wall of the gastrointestinal tract (intestinal first-pass metabolism)
-Destruction within the liver (hepatic first-pass metabolism)
Causes of loss in oral bioavailability equation?
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Calculation of bioavailability (F) based on plasma concentrations?
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what is Lipinski’s “Rule of Five”
Is an empirical rule to evaluate druglikeness or determine if a chemical compound has properties that would make it a likely orally active drug in humans
(Lipinski’s “Rule of Five” ) An orally active drug should have no more than one violation of the following criteria:
- Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)
- Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)
- A molecular mass less than 500 daltons
- An octanol-water partition coefficient (log P) not greater than 5
Biopharmaceutics, Classification System (BCS)
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Biopharmaceutics Classification System (BCS)- High solubility criteria?
A drug substance is considered “highly soluble” when the highest dose strength is soluble in 250* ml or less of aqueous media over a pH of 1-7.5 at 37°C
Biopharmaceutics Classification System (BCS)- High permeability criteria?
A drug substance is considered to be “highly permeable” when the extent of absorption in humans is determined to be ≥ 90% of an administered dose based on mass balance determination
