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
what is the equation for the apparent permeability of a drug
Papp= dQ/dt 1/CoA
- papp= permeability coefficient
- dQ/dt= rate of transport across the membrane
- Co= initial donor concentration
- A = surface area of monolayer
what is the correlation between absorption in humans and log Papp
sigmoidal curve
what is the typical Papp value
2.0 x 10-6cm/s
what are the advantages of Caco-2 model
- can give mechanisms of drug absorption
- non animal
- can use small amounts of drug
- rapid screening of many potential new drugs
- potential toxicity can also be seen
what are the disadvantages of the Caco-2 model
- paracellular route too tight for intestine and no mucus
what tissue techniques can be used for permeability
- diffusion chamber
- perfusion studies
- drug absorption calculated from rate of disappearance of the drug from perfused section
where does pre systemic metabolism occur in oral absorption
- gut wall
- liver
what can be used for measuring pre systemic metabolism in the gut wall
- brush border membranes
- gut wall homogenate
what can be used for measuring pre systemic metabolism in the liver
- liver microsomes- phase I
- isolated hepatocytes- Phase I and II
- liver slices- phase I and II
what are brush border membranes
vesicles will retain the enzymes on the outer and inner surface
- then can look at any metabolism that those enzymes may be responsible for
what are liver microsomes
- made up of membranes of the endoplasmic reticulum
- can only model metabolic processes, because it deals with the membrane not the cytoplasm
what is physiologically based pharmacokinetic modelling
describes the concentration profile of drug in various tissues over time on basis of:
- physicochemical properties of drug
- site and means of administration
- physiological processes to which drug is subjected
what are the parameters from in vitro experiments used for
used in silico models to predict in vivo data
what are the plots for the biopharmaceutical classification scheme graph
- solubility on y axis
- permeability on x axis
describe the effect of food on absorption of furosemide and bumetanide
- bioavailability is reduced in fed state compared to fasted state
- maximum concentration is higher in fasted state
- time taken to reach maximum concentration is slower in fed state
- but food has a much bigger impact on bioavailability of furosemide compared to bumetanide
describe the effect of disease on bioavailability in chronic heart failure patients
- lower Cmax
- longer Tmax
- CHF leads to a decreased ability to transport drug into urine compared to healthy subjects
what are the likely reasons for the effects of chronic heart failure on bioavailability
- delayed gastric emptying
- decreased GI motility
- decreased renal function
- bowel wall oedema associated with CHF
