Physiological factors affecting drug absorption after oral administration Flashcards
Parameters which determine gastrointestinal absorption of drugs
anatomy/histology
physiology
pathology
drug interactions
food (fed vs. fasting)
gastrointestinal transit
metabolism within the gastro-intestinal tract
first-pass effect in the liver
enterohepatic recycling
active secretion (p-glycoprotein, Pgp)
Gastric transit and drug absorption
Stomach: important organ for digestion of food
grinds large pieces of less well-chewed food and breaks food up by chemical decomposition
Gastric fluid is acid and contains a particularly active enzyme called pepsin
some drugs are degraded by the acidic conditions in the stomach
as a result, pharmaceutical scientists have developed gastro-resistant dosage forms which do not release the drug in an acidic environment
other drugs, such as polypeptides, are completely degraded by pepsin
consequently, the oral route of administration is impossible and an alternative must be found; e.g., insulin is routinely administered by subcutaneous injection
However, drug absorption across the stomach wall does not contribute significantly to the oral absorption of drugs
drugs are principally absorbed in the small intestine
GI Tract Motility: Gastric Emptying
Meal volume: the larger the meal, the quicker the initial emptying rate.
Type of meal:
– fatty acids reduce emptying rate, proportional to concentration and chain length (most influence when carbons = 10 or more).
– triglycerides reduce emptying rate; unsaturated more so than saturated (olive and linseed oils most effective).
– carbohydrates and amino acids reduce emptying rate in a concentration-dependent manner (osmotic pressure).
GI Tract Motility: Gastric Emptying
Physical state of contents: solutions or suspensions of small particles empty quicker than chunks of material.
Chemicals: acids reduce emptying rate (conc.-dependent) while alkalis increase emptying rate at low (1 %) concentrations and decrease it at higher (5 %) concentrations.
Drugs: anticholinergics, narcotics and ethanol reduce emptying rate.
Body position: lying on the left side reduces emptying rate.
Disease: emptying rate reduced by the presence of ulcers and in some diabetics.
Exercise: vigorous exercise reduces emptying rate.
The gastrointestinal tract exists in order to break down nutrients in our diet into molecules that are small enough to be absorbed. Drugs resembling nutrients such as proteins, fatty acids or nucleotides are particularly susceptible to enzymatic degradation.
Stomach: Hydrochloric acid – degrades some drugs, so gastro-resistant coatings are used to protect the drug and delay release. Pepsin – a powerful digestive protease. Destroys polypeptide drugs (e.g.insulin), but small peptides survive.
Duodenum: Trypsin, chymotrypsin, elastase and carboxypeptidase A & B are found in the lumen. Degrade 30-40 % of large proteins to small peptides within 10 mins. Small peptides are stable.
Small intestine: High expression of cytochrome P450 enzymes, particularly CYP 3A4, in the intestinal epithelial cells. Highest concentration in the villus tips of the upper and middle third of the intestine. Esterases and glucuronosyl transferases are also present. The latter transfer glucoronic acid to nucleophilic sites on drugs.
Colon: Metabolic activity gradually decreases from the duodenum to the colon. Absorption remains good, however, potential to bypass metabolic degradation and target colonic absorption for peptide delivery. Gut flora can metabolize and inactivate drugs.
Hepatic First Pass Effect
After passage across intestinal membrane, drug is transported to liver via portal vein.
During first passage through liver, a fraction of amount of drug absorbed is transformed into metabolite(s)
which can be active or inactive
So in some cases this first pass through the liver greatly reduces the bioavailability of the drug (First pass effect).
During first passage through liver, a fraction of amount of drug absorbed is transformed into metabolite(s)
which can be active.
Enterohepatic Recycling
Some drugs are eliminated in part by biliary secretion.
Certain drugs, eliminated in this way into small intestine, may then be absorbed again and reach systemic circulation.
Known as enterohepatic recycling.
Amount of drug absorbed depends on:
its release from the dosage form,
stomach, intestinal and hepatic (first pass) metabolism, and
its permeation through the GI membrane.
Transport of drug across the GI membranes
Sometimes removal rate of drug from inside cell is far more efficient than rate of entry.
Good protective mechanism for cells.
Prevents toxic compounds from accumulating intracellularly.
Reason why some tumor cells are resistant to anticancer drugs – drugs transported into cell are removed so efficiently that concentration never gets high enough to be effective.
Specific transport protein = multidrug resistance protein.
Numerous cellular proteins can prevent intracellular accumulation of drugs by pumping drug that enters cell right back out.
These proteins are called efflux pumps.
P-Glycoprotein (PGP)
Example of efflux pump.
One of the most important is p-glycoprotein (p-gp), present in many different tissues (e.g., intestine, placental membrane, blood-brain barrier).
P-gp: responsible for poor bioavailability, low CNS concentration of numerous drugs.
Delayed absorption
Two pharmaceutical dosage forms may show the same rate of absorption, but
achieve identical Cmax values at different Tmax due to a significant lag-time.
Different 1st-order absorption rates
Pharmaceutical dosage forms may have different 1st-order absorption rates.
For most drugs administered orally, the rate of absorption is greater than the rate of elimination.
1st-order and zero-order absorption
Zero-order
amount released per unit time is constant over period of absorption.
achieved, for example, by a paricular tablet coating method.
1st-order
amount absorbed per unit time depends upon quantity (and hence the concn) of drug present at site of absorption.
greater the amount to be absorbed, faster the absorption rate.
