Bioavailability of diuretics Flashcards
why is the bioavailability of an oral solution likely to be less than that of an oral tablet
- tablet is more protected as its a solid so it can’t be attacked or hydrolysed as its is not in solution
what might cause the bioavailability of an oral tablet to be less than the oral solution
- coating might not disintegrate or dissolve completely
what can mean urinary excretion be used for
- assume appearance in urine is a function of extent and rate at which drug appears in systemic circulation
- measures bioavailability - measure concentration of intact drug or metabolites in urine
- metabolite can only be measured if no pre systemic metabolism
what is absolute bioavailability if using plasma concentration data
F= (AUC)absorbed/(AUC)IV bolus
what is the absolute bioavailability if using urinary excretion data
F= (Xu)absorbed/(Xu)IV
When a drug in solution is injected intravenously it has good bioavailability, but when taken orally the bioavailability is reduced. Why
- oral solution could be completely absorbed and metabolised in liver or gut wall
- pre systemic metabolism - may not be stable in GIT, so loss occurs
- drug has to be absorbed and cross the membrane
- if it doesn’t have the right physicochemical properties, it won’t cross the membrane as effectively
- this doesn’t need to happen in IV
what needs to be considered in the measurement of biopharmaceutical properties
- release of drug from its dosage form- dissolution
- stability in physiological fluids
- permeability
- pre systemic metabolism
what does the biopharmaceutical class boundary define as high solubility
- a drug substance is considered highly soluble when the highest dose strength is soluble in 250ml or less of water over a ph range of 1-7.5 at 37 degrees
what does the biopharmaceutical class boundary define as highly permeable
a drug substance is considered highly permeable when the extent of absorption in humans is greater than 90% of an administered dose, based on mass balance or compared with an IV reference dose
what does the biopharmaceutical class boundary define as rapidly dissolving
when 85% or more of the labelled amount of drug substance dissolves within 30 mins using USP apparatus 1 or 2 in a volume of 900ml or less of buffer solutions
what is dissolution testing used for
- formulation development
- product characterisation
- quality control
- batch to batch reproducibility
- stability testing
- shelf life determination - impact of manufacturing changes
how is release of drug from its dosage form different to dissolution testing
- mimics conditions of gIT
- in vitro-in vivo correlation essential
- only likely if dissolution is rate limiting step
- replacement of some animal and human studies
what is a correlation
a mutual relationship or link between 2 or more things
what can be altered to improve the in vitro-in vivo correlation for drug release
- add in a weak acid
- simulate fed state
- stir fast/slow
- choosing volume of medium (250ml as recommended by BCS)
- duration of test
what dissolution medium should be used for in vitro-in vivo correlation study of drug release
- use biorelevent media
- simulate GI fluids in fed and fasted state
- gastric- dilute HCL pH1.2
- intestinal- phosphate buffered solution, pH 6.8 - or consider: pH, ionic composition, surface tension, buffer capacity
- homogenise the meal to be used in clinical study
- use lifelong milk
describe what occurs when a patient takes the solid dosage form
- solid drug ends up in stomach
- dissolution occurs and drug is dissolved in stomach
- gastric emptying occurs and dissolved drug in small intestine
- excretion and absorption of drug in plasma
- calculate PK profile
what class is furosemide in biopharmaceutical classification scheme
class IV
- Low solubility
- low permeability
what volume of medium and agitation should be used for improving vitro-in vivo correlation of drug release
- can use 500, 900 or 1000ml
- BCS recommends 250ml
- gentle agitation
what is the duration of the test dependent on
- site of absorption
- timing of administration
- if absorption is in upper intestine
- if dosed in fasted state
what is involved in measuring stability in physiological fluids
- chemical stability across pH range of gut
- enzymatic stability
- GI fluids
- incubate with real or simulated GI fluid, 3 hours at 37 degrees
- bacterial enzymes
what are the models to predict or measure permeability
- computational
- physicochemical
- biological
- in vitro:
- cell culture
- excised tissue
- in situ studies
- in vivo studies:
- animal
- human
what are the physicochemical approaches to predict permeability
- partition coefficient
- shake flask method
- computational
- HPLC
- immobilised artificial membranes
what are the cell culture techniques for predicting permeability
- Caco 2 cells
- take a layer of epithelial cells which have tight junctions and microvilli
- mimics cells of small intestine
- can conclude likely to be permeable if we can see it in the bloodstream
what is a transport experiment
- where liquid is put in the top chamber (donor chamber)
- measure its appearance in the receptor chamber
