✋ SITE OF ADMINISTRATION TO SYSTEMIC CIRCULATION ❤
DEFINITION ⁉
PROCESS OF OVERALL ABSORPTION 🍖
BIOAVAILABILITY
RELATIVE BIOAVAILABILITY
BIOEQUIVALENCE
FIRST-PASS METABOLISM
ENTEROHEPATIC CYCLING
ABSORPTION
RATE LIMITED ABSORPTION FROM SOLUTION 🤐
PERFUSION
PERMEABILITY
FACTORS OF INCOMPLETE GASTROINTESTINAL DRUG ABSORPTION 😮
RELEASE AND TRANSMEMBRANE RATE LIMITATION IN ABSORPTION
PERFUSION
PERMEABILITY
EFFECT OF FOOD 🍚
CONCENTRATION-TIME CURVE
FOLLOWING A SINGLE ORAL DOSE
ENTEROHEPATIC CYCLING IS EXTENSIVE
systemic - into bloodstream
passage of compound from site of administration
usually across membrane
GENERAL
extravascular
intravascular
intravenous
more common
veins have larger volume
intra-arterial
arteries have smaller volume
used in cancer to deliver to tumro
most drugs act systemically
systemic absorption is required for therapeutic response
any route other than directly into the bloodstream
subcutaneous - into fat
drug intent to act locally
eye drops
systemic absorption is a safety issue
my word: fraction of a dose that reach the systemic circulation in the original form
oral
topical
inhaler - into lungs
ear drops
GENERAL
extent of absorption
rate of absorption
OFTEN USED FOR EXTRA-VASCULAR DOSE
ABSOLUTE BIOAVAILABILITY
extravascular dose to an intravenous dose
ratio of urine A_e infinity
ratio of plasma - AUC
calculate the amount absorbed relative to amount released
when an amount of drug remaining in a use delivery system
transdermal system
permits distinction between release and entry into body
PRODRUG
drug without activity
bioavailability is based on measurement of active metabolite
intravenous reference is the active metabolite
amprenavir
comparison bioavailability between
formulations or drug
given by
same
or different routes of administration
situations
oral tablets vs intramuscular solution
oral tablets vs. oral capsule
used when?
when no intravenous formulation is available
when only comparative information is needed
formulations
same dose
same chemical entities
same dosage form
intended to be interchangeable
situation
different batches or formulations of a test drug are used in clinical trial b4 marketing a drug
when innovator company wants to produce a new formulation for marketing - different from that used in clinical trial
generic substitution - marketed medicinal product comes off patent
standard
test preparation - considered to be therapeutically equivalent
differ by no more than ~20% in exposure profile relative to the reference product
based on AUC -overall exposure of drug
C max
to some degree t max
reference product - innovator's product on which original clinical trials were conducted
in vivo bioequivalence testing
in vivo testing in human volunteer
concentration of the active drug ingredient
its metabolite in
measured as function of time
whole blood
serum
plasma
urine excretion of
active drug ingredient
its metabolites
definition of in vivo testing human
an appropriate acute pharmacological effect of active drug ingredient or its metabolites
measured by function of time
should be measured with
sufficient accuracy
sensitivity
reproductivity
well controlled clinical trials
in patients
establish in drug product
safety
effectiveness
in vivo in a suitable animal model is also approved by the FDA
TYPICAL EXAMPLE
24 - 36 healthy adult volunteer
cross-over design
eliminate variables
drug given to same individual at different time
click to edit
single doses of test and reference drug administered in fasting state
serial samples collected over enough time to estimate
peak concentration C max
AUC for a time period at least 3 x the half-life
total area under the concentration-time curve
equivalence of two pharmacokinetic measures
AUC - extent of absorption
C max - rate of drug input
assessed by statistical procedures
TYPES OF ABSORPTION
TRANSCELLULAR - permeation
passive diffusion
active transport
passive facillitated transport
PARACELLULAR
transport
always passive
VASCULAR ABSORPTION
predominates over lymphatic absorption
blood flow is many times greater than lymph flow
DEFINITION
drug absorption from solution
blood flow - perfusion
membrane permeability
small liphophilic molecules passing thru membranes
small hydrophilic molecules - readily pass thru pores/channels btw cells or membrane (intestinal epithelium)
membrane is not effective barrier to drug molecule
absorption rate depend on the rate of blood flow
polar hydrophilic compounds
Quaternary ammonium compounds
some antibiotics
diuretics
click to edit
move across anymembranes
intestinal tract
pore size 0.6 nm
poorly permeable due to membrane
not depend on changes of blood flow
also dissolution from the drug itself (insert graph here)
Gastrointestinal tract
INTESTINES
large intestines - low permeability
DRUG DESIGN CONCERNS
formulations designed to make drug release rate-limiting step in drug absorption
modified-release formuation
modified-release devices
oral administration - how guarantee
sustained
reliable absorption of drug
over extended periods of time (12h)
time of the material
limited time
in the GI tract
variable permeability of the epithelium down the GI tract
most of the time decrease
variable time
small intestines - high permeability
stomach
gastric emptying
given orally
all drugs absorbed in the small intestine faster than stomach, regardless of pH
rate may impact systemic kinetics of the drugs
in solution form
in solid dosage form
stomach absorption has lower drug absorption
thicker membrane
susceptible to hard and sharp objects
gastric mucus
characteristic impacts drug absorption
low surface area
low blood flow
low permeability
characteristics
3x surface area
2x blood flow
3x permeability
some drugs slow gastric emptying
anticholinergics
narcotic analgesics
some drugs speed up
metoclopramide
CAUSES
lack of time
dissolution - sparingly soluble drugs
excreted in feces or urine
release - controlled release products
membrane permeation
polar drugs - neomycin
even given in solution
move thru membrane too slowly
some other problems
competing reaction
FIRST APPROXIMATION
low intestinal permeability drugs
so much that they're restricted in intestine
maximum extent of absorption
limited by
intestinal permeability
small intestine transit time
these drugs are not candidates for formulation as modified-release products
gastric pH - instability
substrate for intestinal enzymes/ microflora
complexation
reaction
adsorption
conjugation
sulfocojugation
glucoronidation
decarboxylation
efflux transport
hydrolysis
acid
enzymatic
oxidation
reducrion - microflora
hepatic and gut wall extraction
low bioavailability occur in drug - when given orally
first pass effect
enterohepatic cycling (not cause for lack of absorption)
drugs concentrated in the bile
active transport from the sinusoids of the liver to the bile canaliculi across the haptocyte
drug must be a substrate for secretory mechanism
acidic
basic
neutral molecules
high biliary excretion
molecular weight greater than 250 g/mol
polar
ex: glucuronide
polar
ionized acids
high molecular weight >300 g/mol
direction
drug - liver - bile - gall bladder - intestine - portal circulation
drug stored in gallbladder
till emptied by food
complete the enterohepatic cycle
if not absorbed by GI tract, bilary excretion is elimination drug from body
METHOD OF FOOD-DRUG INTERACTIONS
poor acid stability
long exposure to acid lead to
chemical degradation
reduced bio availability
action - take on empty stomach
azithromycin
chelation
drugs
bisphosphonate
ciprofloxacin
norfloxacin
penicillamine
reduced therapeutic effect
action - take on empty stomach
acid dependency
drugs
amprenavir
itraconazole
ketoconazole
depends on acid environment
action
take with meals
if no meals - take at consistent time
bile acid/ fat enhanced drug dissolution
drugs
acitretin
tacrolimus
enhanced bioavailability
action
take with meals
if no meals take at consistent time
physical binding
digoxin
digoxin bind to fiber - bioavailability reduced
action
avoid concurrent ingestion with fibers
take drug consistent with time w/ meals