Processes of drug absorption Flashcards
how is an aqueous solution absorbed after administration?
drugs must be in solution to be absorbed in the body - this usually requres the process of dissolution. however an aqueous solution already contains the drug in solution so it is the fastest route of administration to get a solution of drug in the GI fluids ready for absorption.
what can affect the absorption of an oral aqueous solution?
you may get some precipitation leading to a suspension of fine particles in GI fluids that must then dissolve before absorption can occur.
how is an aquoes suspension absorbed?
when you take an oral aquoesu suspension you get a suspension of fine particles in the GI fluids - this must then dissolve to form a solution of drug in GI fluids to then be absorbed.
how is an immediate release dosage form absorbed?
the immediate release dosage form will form aggregate granules, then a suspension of fine particles in the GI fluids then a solution of drug in GI fluidswhich can then be absorbed.
what is a solution?
a molecular dispersion formed by 2 or more components which form a 1 phase homogenous system - this can be applied to solid liquid and gaseous state.
whats a solvent?
a solvent is the component that determines the phase of the solution - it usually constitutes the largest proportion of the system.
what are solutes?
other components of the solution that are dispersed as molecules or ions throughout the solvent.
whats a saturated solution?
a solution is saturated when the solute is in equilibrium with the solid phase.
what is solubility?
the maximum mass/volume of solute that will dissolve in a given mass or volume of a solvent at a particular temperature. it is the concentration of solute in a saturated solution at a certain temperature.
whats a supersaturated solution?
a supersaturated solution contains more of the dissolved solute than it would normally contain at a definite temperature. for example salts like sodium thiosulphate dissolve in large amounts at an elevated temperature, upon cooling they fail to crystallize from the solution hence they will be at a higher concentration than usual.
whats molarity?
the number of moles of solute in 1L of solvent
whats molality?
the number of moles of solvent in 1kg solvent.
name some other liquid systems that are not solutions
disperse systems with two phases (emulsions and suspensions)
colloidal dispersions (2 phases)
solutions of macromolecular material like polymer material
association colloids like micelles
microemulsions: 1 phase that is isotropic hence its both homogenous and heterogeneous.
what is dissolution?
the process by which the drug particles dissolve - it must dissolve in the fluid at the site of absorption in order for absorption to occur.
describe the dissolution process
the drug molecules in the surface layer dissolve to form a saturated solution around the particle called the diffusion layer. dissolved drug molecules then pass throughout the dissolving fluid to contact absorbing mucosaand are absorbed. there is continued replenishement of the diffusing layer by further drug dissolution so absorption continues until all the drug is absorbed/dissolved.
The rate of dissolution is determined by the slowest steps, what are the steps involved and which one is rate limiting?
step 1 - release of solute molecules from the solid phase at the interface.
step 2 - solution in contact with the solid becomes saturated (Cs)
step 3 - solute molecules migrate through the diffusion layer - from the solid-liquid interface to the bulk of the solution (C)
the interfacial steps 1 and 2 are virtually instantaneous - the rate of dissolution is therefore determined by the diffusion of the solute through the static boundary layer - stp 3 .
diffusion follows ficks law - what is this?
J = (DxKxAx^C)/h
what can you see from ficks law?
the rate of mass transfer through a diffusion layer is directly proportional to the area for migration and the concentration difference whilst its inversely proportional to the thickness of the diffusion layer.
whats the noyes whitney equation for drug dissolution?
dm/dt = k A (Cs-C)
dm/dt is the mass of solute passed int solution per unit of time
how can dissolution rate be increased?
increasing the surface area of the drug (by reducing particle size), increasing the drug solubility in the diffusing layer and increasing K.
whats the dissolution rate constant?
k = D/Vh
how can dissolution rate be raised?
by increasing k - this would involve drug diffusion coefficient and the diffusion layer thickness.
drug bioavailability relies on both absorption and dissolution. how may these affect the bioavailability?
if a drug has high dissolution rates or is delivered already in solution, the rate of absorption relies on its ability to transverse the absorbing membrane.
Where as if drug dissolution is slow, dissolution may be the rate limiting step of absorption.
what factors affect the dissolution rate?
- surface area of the undissolved solid which is influenced by size of particles, porosity, dispersibility and surfactants.
- solubility is dissolution medium affected by the nature of the solute and solvent and pH
- concentration in the bulk solutionaffceted by the volume of dissolution, absorption and GI fluid available
- diffusion coefficient of the solute in the solvent - affected by the viscosity of the solvent and presence of food.
- thickness of boundary layer - affected by stirring and GI motility.
how does particle size affect dissolution rate?
a reduction in particle size increases the dissolution rate due to increased exposure of solute to solvent. if particle size is les than 0.1 um solubility will also be increased.
sodium sulphate is a decahydrate - how does this affect its dissociation?
initially dissociation in water is endothermic - its solubility increases with temperature rise until 32.5, the solid is then converted into the anhydrous form so dissolution is exothermic.
using the salt form of a drug can increase solubility, however in some cases we may reduce the aqueous solubility through esterification of the parent drug for a variety of reasons?
- masking the taste e.g chloramphenicol palmitate is used rather than base form.
- protect from GI degradation e.g. erythromycin propionate instead of erythromycin although this form is less soluble and less readily degraded.
- facilitate absorption from the GI tract e.g the use of erythromycin proprionate as its more readily absorbed than erythromycin.
how does the salt form increase solubility?
using a salt form rather than a weak acid helps solubility as the salt has a higher degree of dissociation in water leading to an increased interaction with the solvent and increased solubility.
whats the difference between simple and stratified epithelium?
simple epithelium is just one layer of cells whilst stratified epithelium is greater than 1 layer of cells
different parts of the body have different epithelium for different functions. explain how the epithelium is different and why for the alveoli, skin and the gi tract.
- the alveoli has a single layer of squamous epithelium to aid gas exchange - this can make drug absorption accross the airways rapid.
- the skin is very thick with stratified squamous epithelium to provide the body with a protective layer - this also means drug absorption accross the skin is relatively slow.
- the gi tracthas columnar epithelium built for absorption of nutrients making it ideal for drug absorption. within the columnar epithelium are goblet cells that secrete mucus into the GI tract.
what steps are involved when a drug is taken orally?
the oral dosage form must be released from the dosage form and then absorbed across the epithelium into the systemic circulation - the slowest step controls the overall rate of absorption.
what are the two pathways in which a drug may be absorbed accross the epithelium?
transcellular - the drug travels through the epithelial cell - this is the usual pathway.
paracellular - the drug goes between two epithelial cells.
there are a number of barriers a drug must cross to undergo paracellular absorption, what are they?
- tight junctions - the membranes of neighbouring cells are fused together by intimate connections between cell surface proteins forming a band around the entire cell. this is the rate limiting step for the paracellular pathway. tight junctions allow the passage of small hydrophilic molecules generally less than 1000 Da.
- adherens junctions - these connect actin filaments of neighbouring cells together.
- desmosomes - these are the most common cell junction - fibrous proteins cross the gap between cells and anchor keratin filaments in the cytoskeletons together.
- gap junctions - these are intercellular hydrophilic pores. membranes close together but not fused. they allow small molecules like amino acids sugars nucleotides and vitamins to pass directly between neighbouring cells. it also enables direct cell to cell electrical conductance.
describe the purpose and functions of the cell membrane
the cell membrane separates the interior of the cell from the surroundings nd transmits information from the exterior environment and neighbouring cells. it provides shape and anchorage points for attachment to the extracellular matrix and neighbours.
the cell membrane is selectively permeable allowing some substances to enter the cell but not others. it also regulates the transport of moleculesinto and out of the cell using carrier proteins, channel proteins and ion pumps to maintain chemical and electrical potentials.
whats the main obstacle in drug absorption?
the lipid bilayer of the cell membrane is the major obstacle in drug absorption - its hydrophobic nature prevents the passage of most polar and charged molecules.
transcellular absorption involves going through the epithelial cells . what are the different ways in which transcellular absorption can occur?
- passive diffusion - solutes diffuse into cells down a concentration gradient, the drug must be lipophilic enough to partition into the lipid bilayer but not too lipophilic as they must then exit into the cytoplasm.
- aqueous pore - a hydrophilic channel created by transmembraen aquaporin proteins. it allows the transport of very small hydrophilic molecules or small neutral molecules like urea and glycerol.
- facilitted diffusion - a carrier mediated transport of a drug down a concentration gradient - it is selective so the drug must be a substrate of the carrier protein.
- active transport - this is carrier mediated transport of a drug down or against a concentratin gradient. it requires an energy input e.g from the breakdown of atp to adp. once again its selective so the drug must be a substrate.
why do facilatated diffusion and active transport eventually come to s astop?
as they are carrier mediated they can become saturated at which point diffusion would stop.
what is endocytosis?
endocytsois is a minor pathway of drug absoprtion in which the plasma membrane is intenalised hence engulfing extracellular fluid. it can then be released from the vesicle from the basolateral membrane. however sometimes the endosome may fuse with lysosomes and the contents are then degarded by lysosomal enzymes.
what is pinocytosis?
cell drinking - small solutes or fluid is engulfed into the cell - this is a constant process and is adsorptive or receptor mediated.
what is phagocytosis?
engulfement of particles by monocytes and macrophages - it is not relevant to soluble drug absorption but significant for advanced delivery systems.
how does passive diffusion occur?
when a system is not in equilibrium it will move toward equilibrium hence when theres a concentration gradient, flux will occur - flux is proportional to the concentration gradient.
what equation can you use for diffusion and what does tgis tell us about the parameters?
Ficks first law of diffusion - it shows that increasing the membrane thickness will reduce flux whilst increasing the area of the membrane will increase flux.
what does the stokes einstein equation?
the stokes einstein equation relates diffusivity to environmental conditions, properties of the medium through which diffusion occurs and properties of the diffusing molecule.
surfactants can lower viscosity to increase diffusivity.
why is diffusion not a fully efficient process?
molecules are blind and move randomly hence in an ensemble of molecules undergoing diffusion the mean displacement x is proportional to the square root of time.
in ficks first law of diffusion, what does the partition coefficient K quantify?
K quantifies the distributionof a drug between the aqueous phase and the membrane - this is analogous to the oil/water partition coefficient P.
How is the oil/water partition coefficient P claculated?
Mix a drug in water then mix this solution with oil. you then leave this solution to settle and separate the layers that form. measure the concentration of drug in the water and the oil to see how the drug is distributed.
the oil/water partition coeffient is often expressed as logP, what doe the range of values of logP mean?
- lipid soluble drugs have a log p of greater than 0
- water soluble drugs have a log P of less then 0
equally distributed drugs will have a log P of 0.
what does the log P of drug say about its properties?
drugs with a logP less than 0 (water soluble) will be very soluble but poor partitioning.
drugs with logP greater than 5 are poorly soluble and their partitioning is too good meaning theyre sensitive to metabolism.
the optimum range for oral drug delivery is logP 0 to 3.
most drugs are weak acids or bases so exist in solution as an equilibrium of unionized and ionised forms depending on the pH of the environment and the pKa of the drug. how will the different forms affect the properties of the drug?
- the unionised drug form will be lipophilic and is optimal for membrane transport
- the ionised drug is hydrophilic and will have reduced membrane transport
whats the ph partition hypothesis?
the drug will accumulate on the side of the membrane where pH favours ionization.
what does the pH partition hypothesis not consider?
type of epithelium, surface area of absorption site, active transport of drugs, residence time of drugs at delivery site, mass transfer of fluids.
another limitation of the ph partition hypothesis is the fact charged drugs may form ion pairs with oppositely charged species. give an example of this situation.
chlorpromazine - its positively charged and forms ion pairs with negatively charged alkyl sulphonates. as the carbon chain and concentration of the alkyl sulphonate ion pair increases the lipophilicity of chlorpromazine increases.
why does oral absorption decrease as hydrgen bond acceptors increase?
hydrogen bonds must be broken before the drug can enter the lipophilic plasma membrane.
although lincomycin and clindomycin have very similar structures their oral absorption varies massively - why is this?
lincomycin has an OH group attached making absorption 30% whilst clindomycin has a chlorine molecule instead hence making the absorption 90%.
what is lipinskis rule of 5?
an ideal drug molecule will have a molecular weight less than 500, a logP less than 5, no more than 5 hydrogen bond donors and no more than 10 hydrogen bond acceptors.
whats an exception to lipinskis rule of 5?
compouns that are substrates for biological transporters.
whats the role of dosage forms?
enable accurate dosing, protect the drug during storage and after administration, conceal unpleasant taste or odour, ease delivery and oprimise delivery and release.
what are tablets?
form of drug prepared by compression or moulding - caplets are similar but oval shape makes them easier to swallow. they contain the API and diluents, disintegrants, colourings and coatings.
what are capsules?
the drug and excipients are enclosed in a soft or hard shell made of gelatin or cellulose derivative - generally release API more rapidly than tablets.
what are solutions?
solution is an api in an aqueous vehicle, can also get elixirs the api in a sweetened aqueous alcoholic vehicle or syrups the api in a sucrose based vehicle.
what are suspensions?
fine particles of drug in a suitable vehicle. this is good for drugs that are poorly soluble, allows a larger does to be given than by tablet/capsule, must be shaken, is available for immediate dissolutionand rapid absorption and good for certain patient groups.
what is enteral drug administration?
within or by way of the intestine, oral buccal sublingual rectal
what is parenteral administration?
outside of the alimentary canal - injections infusions and implantable devices.
what organs make up the GI tract?
esophagus carries food to the stomach, the stomach then mixes the food with digestive enzymes and grinds it won into a semi liquid form, the small intestine is the site of absorption for nutrients and the colon reabsorbs water and eliminates indigestable food residues.
the stomach is a muscular sack that acts as a food reservoir and plays an important role in digestion. what does the mucosal lining secrete that can cause issues for drug delivery?
when food is ingested it stimulates the secretion of hydrochloric acid and pepsinogen from the mucosal lining.
the hydrochloric acid acts as an antiseptic and promotes the conversion of pepsinogen to pepsin.
the pepsin (derived from pepsinogen) is a potent proteolytic enzymethat breaks down proteins - its very effective at degrading polypeptides while short peptides can pass through unharmed. the pepsin makes it difficult to deliver protein based drugs like insulin and the acidic conditions can also pose problems for drug delivery.
what can be done to overcome the issues of drug degradation in the stomach?
enteric coatings to protect the drug or use an alternative route of administration.
describe the structure of the small intestine - the main site of food and drug absorption.
the small intestine begins with the duodenum where acid contents of the stomach are neutralized by secretions of bicarbonate enabling optimum enzymatic digestion of food. the common bile duct from the pancreas and gall bladder enters its secretions here. this provides a cocktail of enzynes utilised in the digestion of food including trypsin, chemotrypsin, elastsase, carboxypeptidase A and B, amylase and lipases.
the majority of food absorption occurs in the jejunum while the ileum absorbs any remaining nutrients, particularly fats.
what provides the large surface area of the small intestine, enhancing drug absorption?
the structure of the small intestine provides its large surface area, it has folds and is covered in villi with a good lymphatic system and capillary network. the villi also have a brush border of microvilli once again increasing the surface area.
what are the 2 main functions of the large intestine?
absorption of water and electrolytes as well as the storage and elimination of waste matter. although the colon lacks the villi of the small intestine so has a much lowe surface area.
what does the colon contain that may affect drug bioavailability?
the colon has a high amount of aerobic and anaerobic bacteria that may metabolize drugs by bacterial enzymes. en example is L-Dopa.
explain how drug absorption occurs down the GI tract.
the stomach has a low SA, low blood flow and lining is mainly secretory mucosa hence little absorption occurs here. also the acidic environment means basic drugs will dissolve easily.
the small intestine has a very large surface area with high blood flow and a neutral pH and absorptive mucosa hence most drug absorption occurs here.
the large intestine has much slower drug absorption due to lower surface area.
what is paracellular absorption?
passive diffusion of small hydrophilic drugs like mannitol through the intercellular junctions, down a concentration gradient.
what is transcellular absorption?
- passive diffusion - drug diffuses through apical membrane down concentration gradient based on their lipophilicity and ionisation. it subsequently diffuses through the cell and basolateral membrane.
- active transport - the apical membrane contains a number of transporters - drugs may utilise these if sufficiently similar to the natural substrate.
what would make a drug be poorly absorbed?
if a drug is a strong acid (pka less than 3) or a strong base (pka is greater than 10) it will be poorly absorbed as it will be ionised in the GI tract
How can we work out where a drug will be best absorbed?
By using the drugs pKa and the pH at different locations of the GI tract we can use the Henderson-Hasselbach equation to calculate the percentage of drug in the ionised form. Drugs will be absorbed best in the unionised form, so the pH at which theyre mainly unionised is where they will be best absorbed.
What are the muscular movements of the GI tract essential for?
propelling food and drink through the intestines, mixing intestinal contents with digestive juices and preparing unabsorbed material for excretion.
the movements also move the drug through the GI tract.
what is required for optimal drug absorption?
the drug must have sufficient residence time at its absorption site. If movement through the GI tract is too fast it will pass through without being absorbed, if movement through the GI tract is too slow, the onset of pharmacological effect will be retarded, the drug may be degraded or the epithelium may be irritated.
there are two patterns of GI tract motility: interdigestive and digestive. What is interdigestive?
interdigestive (the fasted state) is alternating cycles of activity called the migrating motor complex, each cycle lasts 90-120 minutes. Phase 1 is quiescence, phase 2 is irregular contractions and phase 3 is housekeeper waves.
Whats the second type of gastric motility, digestive?
digestive is in the fed state where there are 4 to 5 contractions per minute that mix contents and pass them down the tract. the length depends on the type of meal.
the stomach gradually releases its contents into the small intestine (roughly zero order). there are many factors that affect the gastric emptying and therefore drug absorption, what are they?
- meal volume - the larger the meal the quicker the initila emptying rate.
- type of meal - fatty acids reduce emptying rate - this is proportional to concentration and chain length. triglycerides will reduce emptying rates, unsaturated more than saturated whilst carbohydrates and amino acids reduce amptying rate in a concentration dependent manner (osmotic pressure).
- physical state of contents - solutions or suspensions of fine particles empty quicker then chunks of material.
- chemicals - acids reduce emptying rate in a concentration dependent manner while alkalis will increase emptying rate at low concentrations and decrease emptying rates at higher concentrations.
- drugs - anticholinergics, narcotics and ethanol reduce emptying rate.
- body position - lying on the left side reduces emptying as the stomach has to work against gravity to push food through the pyloric sphincter (the sphincter is on the right side)
- disease - the emptying rate is reduced by the presence of ulcers and in some diabetics.
- excercise - vigorous excercise reduces the emptying rate
how can drugs affect the uptake of other drugs (examples)?
taking paracetamol with propantheline greatly reduces the plasma concentration profile of paracetamol.
taking paracetamol with metoclopramide dramatically increases the plasma concentration profile of paracetamol.
liquids and small particles are generally not retained in the stomach as they can exit via the pylorus. this should be considered when thining about dosage form, how would it affect this?
drugs that are rapidly released from the dosage form become a drug in solution in the gastric fluid - this means they can be progressively and rapidly released through the pylorus in a fasting subject. However gastro resisitant dosage forms cannot pass the pylorus as only particles of few mm can exit. they must therefore wait for house keeper waves - this creates a lag time between when the drug was taken and its arrival at the intestinal absorption site.
the gi tract releases lots of enzymes to break down nutrients in our diet into molecules that are small enough to be absorbed. this means drugs resembling nutrients in our diet like proteins fats or nucleotides are particularly susceptible to enzymatic degradation. Outline what enzymes are released from different parts of the gi tract and what their functions are.
- the stomach releases hydrochloric acid that can degrade drugs henc a gastro resistant coating can be used to protect the drug and delay release.
- pepsin is released by th stomach - this is a powerful digestive protease, it destroys polypeptide drugs like insulin although small peptides can survive.
- trypsin, chymotrypsin, elastase and carboxypeptidase A and B are found in the lumen of the duodenum. these degrade 30-40% of large proteins to small peptides within 10 minutes - the small peptides are then stable.
- the small intestine has a high expression of cytochrom P450 enzymes, particularly CYP3A4 in the intestinal epithelial cells. the highest concentration is in the villus tips of the upper and middle third of the intesti9ne.
- the small intestine also has esterases and glucuronosyl transferases - the glucuronosyl transferase transfers glucuronic acid to nucleophilic sites on drugs.
- the metabolic activity decreases gradually from the duodenum to the colon. absorption remains good - it is possible to bypass metabolic degradation and target colonic absorption for peptide delivery, although the gut flora present can metabolize and inactivate drugs.
where does the liver get its blood supply from? what does this mean about the liver? how does blood then leave the liver?
25% of blood to the liver comes from the hepatic artery supplying oxygenated blood whilst the remaining 75% comes from the portal vein bringing venous blood from the GI tract. this means the liver is the first line of defense for substances that are ingested.
the blood then leaves the liver via veins which drain into the inferior vena cava.
what are the most common metabolic reactions in the liver that affect drugs?
oxidation reduction conjugation and hydrolysis. metabolic transformations usually result in the formation of a more polar metabolite that is pharmacologically inactive.
what is the first pass effect?
when drugs are absorbed in the GI tract they go to the liver in the bloodstream here they may then get degraded through metabolism making them ineffective. this means a smaller fraction of drug reaches the systemic circulation and distributed around the body.
how is clomipramine affected by the first pass effect?
clomipramine is an antidepressant - the principal metabolite desmethyl clomipramine is active hence the dosing regiment remains the same when changing route of administration.
how is haloperidol affected by the first pass effect?
haloperidol is an antipsychotic, 50% of the drug is lost due to the first pass effect, however there is no loss when administered by intramuscular injection. the dose will therefore need adjusting accordingly on change of route.
it is important to consider how other medications the patient is taking could affect the bioavailability - give an example where this is the case.
the bioavailability is more than 2 fold lower in epileptic patients compared to healthy individuals due to drug interactions. it is therefore important to consider this when deciding dosages.
what 3 passages does a drug make when taken orally that could affect the fraction that reaches systemic circulation?
a digested drug could be degraded/metabolised in the stomach, then in the intestines and finally they could undergo hepatic first pass metabolism.
how do you calculate the fraction of drug reaching systemic circulation (F)
F = fraction of drug absorbed x fraction of drug escaping hepatic first pass metabolism
If F is too low we may want to find an alternative administration rout and adjust the dose appropriately.
the gall bladder releases bile into the small intestine - what does this do?
the bile is lipophilic and hydrophilic so it acts like a detergent to help fats mix with aqueous liquids. it also facilitates the excretion of a number of endogenous and exogenous compounds and aids digestion of fats and fat soluble vitamins.
how are bile acids recycled?
only 5% of bile acids is lost through faecal elimination - the rest goes into the portal circulation from the small intestine back to the liver where it gets filtered into bile ducts back to the gall bladder.
what is enterohepatic recycling?
some drugs may enter the bile and get deposited in the gall bladder. they may then be released by biliary secretion into the small intestine where they may be reabsorbed and reach systemic circulation.
as gall bladder emptying time varies between individuals there may be interpatient variability.
food can impact the absorption and bioavailability of drugs, particularly when the drug is taken with a meal or within 30 minutes of eating. in what ways can food affect absorption rate?
- delayed gastric emptying - this could cause damage to proteins or acid labile drugs.
- stimulation of bile secretion can increase solubilisationand absorption of lipophilic drugs like griseofulvin
- increased viscosity of luminal contents
- stimulation of hepatic blood flow can effect first pass metabolism
- pH changes in the GI tract - a decreased pH may aid the dissolution of basic drugs
- changes in luminal contents
- physical or chemical interactions of the drug with food - a drug may bind to components of a meal and form a non absorbable complex for example tetracyclines interact with divalent cations
- competition for uptake transporters e.g. L-dopa
the largest effects are seen with enteric coated tablets, reduced effects are apparent with well dispersed dosage forms.
how is lapatinib a drug for breast cancer affected by food?
the bioavailability of lapatinib is increased by 167% from the presence of food - this is due to the triggered relewase of bile that helps the fatty drug be mixed and absorbed.
how do polycyclic aromatic hydrocarbons affect drug absorption?
polycyclic aromatic hydrocarbons induce CYP1A1 and CYP1A2 hence decreasing the bioavailability of pheacetin and thephylline.
how does cruciferous vegetables affect drug absorption?
cruciferous vegetables induce the CYP1A enzymes, glutathione-s-transferase and quinine oxidoreductase.
how does salt affect drug absorption?
sodium chloride may increase CYP3A activity at high levels.
how does watercress affect drug absorption?
watercress inhibits CYP2E1
how does red and black pepper and chillies affect drug absorption?
peppers and chillies may inhibit CYP1A CYP2B and CYP2E1.
how does grapefruit juice affect drug absorption?
grapefruit juice inhibits CYP3A increasing the bioavailability of estradiol, felodipine and cyclosporin
what are efflux pumps?
efflux pumps are a protective mechanism protecting the body from toxic foregin compounds as they kick them out of the cells before they can reach a damaging concentration.
what is p-glycoprotein?
p-glycoprotein is one of the ost important efflux pumps. its a 170 kDa protein found in the apical membrane of cells in the small and large intestine - as well as the liver kidney BBB placenta and cancer cells.
P-gp is a multi drug resistance protein - substrates are mainly lipophilic or cationic like anthracyclines, cyclosporin and celiprolol.
why was taxol (an anti microtubule drug) not orally absorbed in preclinical trials?
the flux of taxol from the basolateral side of the membrane back into the lumen was 4 - 10 times greater than diffusion into the intestinal lumen - hence any taxol that entered the cells were removed by efflux pumps like p-gp
what enhances the metabolism of drugs?
p-gp is colocalised with CYP3A on the apical membrane.
submucosal glands and goblet cells secrete mucus along the GI tract - how does this affect drug absorption?
the entire length of the GI tract is coated in a protective layer of mucus - this acts as a barrier to some drugs like warfarin but for other drugs like barbituric acid derivatives it is essential for absorption.
how does gender affect drug absorption?
gastric acid secretion is greater in men and gastric emptying is slower in women. also men have higher levels of CYP enzymes. pregnancy results in reduced gastric acid secretion and increased GI motility.
how does age affect drug absorption?
gastric fluids are less acidic in newborns. children have less tight cell junctions hence they have leaky epithelia meaning they absorb drugs better - this can lead to overdosing and toxicity. elderly people have decresed enzymatic metabolism including first pass.
what ways are ther to improve drug delivery?
- increase drug lipophilicity by using prodrugs
- p-gp inhibitors
- cytoadhesion - target drugs to specific areas of the gi tract
- mucoadhesive patches - to hold drug iin the same location so absorption can occur
- new delivery systems like micro and nano particles and protective coatings
some drugs like antibiotics may be hydrophilic making absorption poor giving them poor systemic bioavailability. how does ampicillin resolve this issue?
as bacampicillin is poorly absorbed you can administer the inactive prodrug bacampicillin - this is much more lipophilic and will therefore cross the cell membrane - it then gets metabolised in the cell to un mask the active drug as an esterase converts bacampicillin to the active ampicillin molecule. the oral bioavailability of ampicillin is 30-50% - this increases to 80% when bacampicillin is administered instead.
we can sometimes modify the structure of a drug to improve its absorption. outline two ways in which this can be done.
lipidization involves attaching lipids to the drug. another method is penetration enhancers - these partially solubilise the epithelial membrane to increase absorption.
whats another type of prodrug?
a drug with a cleavable attachment to a biological salt to increase its absorption in the GI tract.
how does pgp affect chemotherapeutic drugs?
pgp prevents chemotherapeutic drugs from entering cancerous cells and also prevents the oral delivery of many anti cancer drugs due to its presence in intestinal epithelial cells.
what can be done to improve the absorption of chemotherapeutic drugs which have interference from pgp?
co administration of pgp inhibitors with chemotherapeutics should prevent drug efflux from endothelial cells and increase oral bioavailability.
what else did first and second generation pgp inhibitors do?
they also inhibited CYP3A4 causing reduced drug clearance.
third generation pgp inhibitors are specific for the transporter and are clinically effective. give an example where these have been successful.
administering topotecan with the pgp inhibitor elacridar increases the oral bioavailability in huans from 40% to 97%.
what are mucoadhesive patches?
mucoadhesive polymers can be utilised to improve residence time of a drug delivery device at an absorption site and bring the drug into close contact with the epithelium. you swallow a capsule that contains small mucoadhesive patches - this is a mucoadhesive polymer containing the drug with a water insoluble coating. they bind to mucus in the GI tract with the insoluble coating protecting the drug and directing its diffusion to the membrane.
