L30/31 - Physiological Factors Affecting Drug Absorption After Oral Administration

• What factors/parameter affect GI absorption of drugs?

  anatomy, physiology, food effect (fasting/fed?), metabolism, first pass effect, enterohepatic recycling, active secretion (Pgp)

  
• What is the Food effect?

  The impact of food on the function and movement of the digestive system.Food affects drug bioavailability
• where are drugs mainly abosrbed?

  small intestine
• What factors affect GI motility hence absorption?- How do they affect the rate of gastric empyting?

  - meal volume: larger the meal, the quicker the initial emptying rate, but then depends on...- meal type: fatty acids, triglycerides and carbohydrates decrease emptying rate- state of contents: solutions empty quicker (increase rate)- chemicals: acids increase rate, alkalis increase rate at [low] and increase rate at [high]- Drugs: eg anticholinergics decrease emptying rate- body position: lying on LEFT side decreases rate- disease or vigorous exercise decrease rate
• What does the housekeeper wave do?

  opens pyloric sphincter so drug can enter small intestine
• How does meal volume affect emptying rate?

  the larger the meal, the quicker the initial empyting rate - then depends on type of food!
• How does type of meal affect gastric emptying rate?

  - fatty acids decrease rate, proportional to [conc] and hydrocarbon chain length- triglycerides decrease rate, unsaturated more so than saturated- carbohydrates/amino acids decrease rate, proportional to [conc]
• How do acids/alkalis affect gastric empyting rate?

  Acids = decrease rateAlkalis = increase rate at low [conc], then decrease rate at high [conc]
• IR vs gastro-resistant tablets- where are they released?

  IR: immediate release, in stomach- in fasting state, drug leaves stomach quickly and rapidly via pylorusGR: Gastro-resistant/enteric coated = same thing- can't pass pylorus, so must wait for housekeeper wave- lag time: slower release into small intestine where it needs to dissolve polymer before absorption- GR gives delayed onset of action, even if same bioavailability due to lag time

  
• BCS class I

  highly soluble, highly permeable

  
• BCS class II

  poorly soluble, highly permeable

  
• BCS class III

  highly soluble, poorly permeable

  
• BCS class IV

  poorly soluble, poorly permeable

  
• How can we improve solubility?

  use salt forms, cosolvents, micelles, inclusion compounds etc
• How can we improve membrane permeability?Eg?

  Use prodrugs to modify structureEg bacampicillin = ester of ampicillin (which has poor oral bioavailability)- ampicillin = principle metabolite - physicochem properties of bacampicillin allow easier passage across intestinal barrierSO bacampicillin delivered, and metabolised to give ampicillin

  
• What enzymes are involved in GI digestion/metabolism in:- stomach- duodenum- small intestine- colon?

  Stomach: HCl, pepsinDuodenum: trypsin, chymotrypsin, elastase, carboxypeptidase A&BSmall intestine: cytochrome P450 , esterases, glucuronosylColon: gut flora can metabolise and inactivate drugs, eg sulfasalazine
• what's the Hepatic first pass effect?

  liver reduces bioavailability of a drug if drug is transformed into inactive metabolite- drug moves to liver from small intestine via portal vein (w/deoxygenated blood)- a fraction of drug absorbed is converted to metabolite (active or inactive)

  
• What's the alternative first pass effect?Eg?

  A fraction of a drug can be absorbed and transformed into an active metabolite by the liverEg clomipramine: principal metabolite is active.Pharmacological activity of metabolite is similar to that of the parent drug- no dose adjustment required
• What's Enterohepatic recycling?

  = recycling in the liver- The reabsorption of a drug from the intestines back into the bloodstream

  
• define exogenous/endogenous

  exogenous = external cause/originendogenous = internal cause/origin
• Describe the process of enterohepatic recycling

  - drugs are transported to liver via portal vein to liver (w/deox. blood from GI tract)- some drugs travel through bile, and are secreted back into the small intestine = second passage, so can be absorbed again by small intestine to reach systematic circulation

  
• What are Prodrugs?


  Inactive compounds that are converted into active drugs in the body
• Trypsin


  An enzyme in the small intestine that breaks down proteins
• Cytochrome P450 enzymes

  Enzymes in the small intestine/liver that metabolize drugs
• What does bioavailability/ amount of drug absorbed depend on?What symbol is sometimes used for bioavailability?

  - rate of release from dosage form- stomach, intestinal and hepatic (first pass) metabolism- rate of permeation through GI membranebioavailability = F

  
• What are efflux pumps?Example?

  proteins that remove drugs from cells= why drugs can't enter the blood-brain barrierEg PGP

  
• Sometimes a drug's removal rate from a cell is more efficient than rate of entry.What are advantages/disadvantages of this?

  - good protective mechanism- prevents accumulation of toxic substances- why some tumour cells are resistant to anticancer drugs: drugs are removed from cell so efficiently that [drug] conc is never high enough to be effective
• What is PGP?

  = P-Glycoprotein- efflux pump protein that prevents the accumulation of certain drugs by pumping them straight out of cells- good for host defense, but responsible for poor bioavailability

  
• what are P-Glycoprotein inhibitors?

  Substances that block the activity of P-Glycoprotein
• PGP prevents chemotherapeutic drugs from entering tumour cells. It prevents oral delivery of many anticancer drugs due to its location in intestinal epithelial cells.How can we overcome this?


  co-administer PGP inhibitors with chemotherapeutic drugsthis should prevent efflux from endothelial cells and increase oral bioavailability

  
• What is the role of the dosage form?

  - enables accurate dosing- protects drug during storage and administration- masks unpleasant tastes/odour- easy delivery- optimise delivery and release, eg IR/MR

  
• Inter- and intra-patient variability


  Differences in drug absorption and response between individuals, and within one individual
• Delayed absorptionWhy might two dosage forms have the same rate of absorption, but have the same Cmax values at different Tmax?

  Lag time!'retard' is often used to describe these dosage forms

  
• What does it mean when the area under two curves on a graph (x=time, y=Cp) is the same?

  The drugs have the same bioavailability

  
• 1st order absorptionwhat is amount absorbed dependent on?

  amount absorbed per unit time depends on [drug] conc present at site of absorption- the greater [drug], the faster the absorption rate

  
• 0 order absorption- how is amount released controlled?

  amount releases per unit time is constant over period of absorption- eg controlled by particular tablet coating methods

  
• How does Presence of Food affect bioavailability?Why is this hard to study?

  Amount of drug reaching systematic circulation may be increased, decreased or unaffected by foodHard to study bc lots of inter/intra pt variability, incl dif eating habits and cultures

  
• How should tetracyclines be taken?

  - on empty stomach to maximise bioavailability- GI absorption significatnly decreased by presence of Al, Ca (dairy), Fe, Mg (antacids)