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Biopharmaceutics
Dr. Rana Abu Dahab
Lecture -6- Menas Abu Alhalawa
We were talking in the previous lecture
about the oral drug absorption and we
mentioned the physiological variables ;
physiological factors that influence drug
absorption from the gastrointestinal tract;
the first one of them is the gastric
emptying, the gastric emptying rate ,the the
presence of food and the gastric
secretions.
We did mention previously that the
duodenum is the major site for absorption
of nutrients, and the major site for
absorption of drugs ; thus the reservation
of the drug in the duodenum crucially
determines the rate of appearance of the
drug in the systemic circulation; So
whatever dose I’m providing the body with
got to get to the duodenum as fast as
possible in order to me to get the highest
rate of drug absorption, so we need that
drug emptying in the stomach and the
intestinal emptying , and any delay in
gastric emptying would delay dug
absorption factors that we said before can
affect the rate but could also affect the
extent. Another factor is how long the
drug’s stable in the stomach.
And we also said that The gastric emptying
rate (gastric emptying time) is a highly
valuable parameter and it’s the cause for
intersubject variability in the plasma
concentration time profile.
Now the stomach differ in the fed and the
fasting statuses; in the fasting status goes
through 4 phases; in the 3rd stage there’d be
an emptying from the stomach to the
duodenum, in order for emptying to
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happen we need contractions of the
stomach and relaxation of the pyloric
sphincter so that there’d be a transfer of
the chime from the stomach to the major
site of absorption, the stomach in stage
1,2,4 isn’t going through any active
contractions (the stomach in an almost
silent position) and we’d wait for stage 3 for
the emptying to happen, and that’s the
cause of the variability when people take
the dosage form at fasting status.
Whilst other statuses(fed statuses) there
are those regular contractions that mixes
the food in the stomach and empties the
food from the stomach to the duodenum
however those contractions and emptying
are dependent on the existing food.
Variability when having a drug at fasting
status comes from the phase (1,2,3 or 4)
we’re in.
So when we talk about mild moderate
meals; light meals like breakfast , then the
drug taken with these meals would go
under contractions and emptying, however
we’re talking about foods that are potent
inhibitors for gastric emptying , and the
drug’s taken after such a large meal; a meal
with inhibitor for gastric emptying again
there’d be a delay for the drug till reaching
the systemic circulation.
The factors that affect the gastric emptying
are numerous and today we’d focus on the
ones that are mostly related to food
starting with 1-the volume of the meal ;
now the gastric emptying is an exponential
process meaning that the more volume the
Biopharmaceutics
Dr. Rana Abu Dahab
Lecture -6- Menas Abu Alhalawa
stomach is being filled with for the first
emptying from the stomach to the
duodenum, now the duodenum with it’s
mechanoreceptors gets stretched and the
mechanoreceptors causes a negative
feedback on the stomach; so the
duodenum whilst emptying of a large
volume alerts the stomach to stop.
Emptying stops to enable the duodenum to
control the amount it already still has , then
there’d be a processing from the stomach
to the duodenum.
Duodenum deals with whatever it has, then
another amount of food empty from the
stomach to the duodenum again for other
process of digestion and absorption.
So, the correlation between the stomach
and duodenum is that the stomach doesn’t
empty until the duodenum is done with
the digestion and the absorption.
One of the important terms is the 1)volume
: for example, after fasting first thing people
tend to do is to drink large quantity of
liquids (which is not recommended claiming
that it causes a premature satiation
feeling; because of the at once
emptying of the duodenum and that’s
it. That the stomach afterwards would
instantly be full.)
secondly2)the type of meal(mostly the
fatty meals; when we’d have large
amounts of triglycerides or unsaturated
fatty acids, that fat is a potent inhibitor
for gastric emptying; mainly digestion of
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fat is slower than digestion of
carbohydrates and proteins, and fat is
absorbed in the duodenum, so
whenever we take a fatty meal due its
slow digestion in the duodenum
whatever is in the stomach doesn’t get
quickly emptied so it prevents the
gastric emptying, so in the case of giving
a solid dosage form along with fatty
meal it’d be waiting for the contraction
for it’s emptying and this explains why
would some people(especially for their
kids) have a fatty nutrients for Suhoor
taking in consideration the time spent
without eating during the day of fasting.
Now, if a unit dosage form (a tablet ;
one not to be dissolved; a coated tablet
form not suspension lets say) was taken
by me after a fatty meal it’s emptying
will definitely be delayed (no rapid
appearance of the drug in the
circulation)
(carbohydrates have less complications
than fats yet have a high osmotic
pressure so are the amino acids osmotic
pressure reduction in the rate of
emptying dependent on the conc. Of
salts and non electrolytes , physical
state of gastric content, the larger solid
is the gastric content the larger gastric
emptying there is; since reducing the
size of big particles is the function of the
stomach, while the emptying would be
fast when we have something like soup
Biopharmaceutics
Dr. Rana Abu Dahab
Lecture -6- Menas Abu Alhalawa
or something sweety for Futoor so the
goal from having soup at first for Futoor
is to have a quick emptying and
absorption for the sugars that’d been
taken the thing that’ll lead to a
refreshing sensation (the secret behind
the importance of starting with
something light at the beginning of the
Futoor)
Food has important function in
terminating gastric emptying and gastric
emptying rates,
Sometimes we actually “recommend
the patient to take the drug along with
food” ; if the drug itself was an irritant
or causes gastric upset, we might need
such recommendations as some sort of
compromising seeking for some sort of
balance even when in this case it might
actually decrease the bioavailability in
exchange for some limitation in the side
effects
And in other times we might need to
rapid the appearance of the drug in the
systemic circulation (we recommend it
taken half an hour before the meal or an
hour afterwards; in case of drug-food
interactions so that there wouldn’t be
any complexations from drug-food
interactions, so we do that to decrease
the effect of food on the rate of
appearance of drug in the systemic
circulation,so this one is of important
biological matters)
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So now, back to Distinguishing in the
gastric emptying between different dosage
forms.
Liquids and small particles usually empty
quite rapidly irrespective of 1)Fed status 2)
if the pyloric sphincter was relaxed or
contracted (11:46) ; so when I take
solutions, or suspensions or dosage form
that rapidly disintegrates in the stomach ,
all of these disperse in the GIT and emptied
irrespective of the fed status meaning that
pyloric sphincter won’t make the stomach
totally sealed; there’s some space which
allows passage of liquids such as water(and
that’s how liquids and small particles are
dealt with during the gastric emptying, no
problems happen)
Now the more sensitive to gastric
emptying are the larger particles the ones
larger than the few millimeters; those need
contraction of stomach along with
relaxation of the pyloric sphincter so that
they transfer from stomach to the
duodenum .
The more challenging would be the nondigestable very large solids just like the
Ibuprofen ®800 tablet and the antibiotic
tablets in grams housekeeper wave that’d
transfer them from the stomach to the
duodenum; what makes them more
sensitive to the gastric emptying in the
presence of food while the small particles
on the other hand don’t really get effected
by that .
Another parameter intestinal motility
Biopharmaceutics
Dr. Rana Abu Dahab
Lecture -6- Menas Abu Alhalawa
Now we previously said that drugs are
absorbed from duodenum.
drug absorption, it’s more of a residual
area for drug absorption.
Now, afterwards the chime reaches the
intestines a sufficient residency must be
achieved in order to absorption to fully
happen; now the drugs are in the lumen of
the intestines in the salts of the chime and
the muscles there are operating the mixing
so drug is mixed and dissolved and during
the mixing also it approximates on the
surface of the mucosa to allow to the
absorption meaning that not everything in
that tube(intestines) is going to be absorbed
that instantly; it actually needs to approach
the mucosa and get absorbed.
So we talked so far about the biological
variable number one : the gastric emptying
and the gastric motility
So Residency in the intestines(which is 34hrs, although it could be prolonged in the
fed status up to 12hrs also in case of any
diseases that residency can be even shorter
than normal) is important for:
–Residency in the intestine allows for
complete dissolution and complete
absorption.
So lets say our patient does have a GIT
disease; an infection or lets assume it’s a
diarrhea in this case: the drug isn’t
supposed to be given orally because there
won’t be a sufficient residency nor suction
for a fully absorption so it’s favored to be
given as injection(if possible).
Then comes The Colon with a residency
time that’s up to 35hrs (longest) influenced
by amounts of food and fibers, it has been
also said that colon isn’t a major site for
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Secondly The effect of food in GIT: (now we
know that presence of food effects the
bioavailability and absorption .
Effects are: 1)Alteration of the rate of
gastric emptying , and usually a delay in the
rate of absorption
An example : (important*)
-The stomach(with it’s acidic PH is excellent
for dissolution of weakly basic drugs )
PROS: the ionized molecules are usually
better dissolved), if we had a weak basic
drug with low solubility then the longer
they stay in the stomach the higher would
be it’s solubility, just like the nitropheratol
which is a weak basic drug with poor water
solubility(which makes it not dissolve in the
duodenum secretions and yet dissolves
better at the lower PH of the stomach; it’s
given with fruit (given with food generally)
so that we delay the gastric emptying
(which would increase it’s dissolution
although I’d witness a reduction in the rate,
but usually the extent is higher) for a
complete dissolution, now since I kept it in
the stomach longer I’d find a lower
absorption at first that’d be lifted by the
extent .
Biopharmaceutics
Dr. Rana Abu Dahab
Lecture -6- Menas Abu Alhalawa
To sum up the example:
Giving the drug with food => delayed gastric
emptying => drug stays in stomach for
longer time => higher opportunity for
dissolution in the acidic conditions of the
stomach => eventually leads to higher
extent of absorption (bioavailability)
because high dissolution which
compensates the delay in gastric emptying.
“Delay in gastric emptying is NOT always
Unfavorable”: meaning we referred to
delay as unfavorable earlier above, but in
this case of a weak basic and poorly soluble
drug(so they’d need to stay longer time in
the stomach to allow their dissolution); so
then it’s favorable.
-if a substance was very ***(18:00) it won’t
be absorbed
2)Stimulation of gastric secretions , a type
of pancreatic secretions which are
important => bile salts that are secreted
upon the ingestion of food especially a
presence of high proportion of fat; now the
structure of bile salts explains their aactivity
as surface active agents, they operate on
fats until they reduce the size of globules of
fatty droplets to allow their digestion then
absorption, because they’re amphephiles
surfactants and improve the dissolution of
hydrophobic drugs , it might be ok with the
ingestion of food along with the given
dosage form; because the bile salts are
capable on stimulating the solublization of
hydrophobic agents , so they may improve
solubility of some drugs of low solubility,
bile salts have short form insoluble
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complexes with some drugs reducing their
bioavailability, they might complex with
drugs forming insoluble complexes (drugs
that form insoluble complexes with bile
salts: neomycin, kanamycin).
Bile salts may improve absorption or
reduces it.
“bile salts always improve drug solubility”
=> this statement is false.
The anti-fungal “ Greaseofalvin” is a very
hydrophobic drug, to overcome this
problem we recommend the patient to take
it with a very fatty meal  a slow emptying
rate, but the presence of the bile salts has
been noted to improve the dissolution of
that drug and improves the bioavailability of
the drug , after the stimulation of secretions
there’d be competition between drugs for
specialized absorption and food
components
If the drug is absorbed by carrier mediated
mechanism and another nutrient existed
which is absorbed by the same mechanism
they may compete.
3)food increases the viscosity of the GI
content and reduction in dissolution rate
and diffusion to reach cell membranes: If
the drug is taken without food and only
with a glass of water then the chime will be
thinner and the diffusion of the drug across
the chime would be faster , diffusion is
dependent on viscosity and the absorption
would be fast however the presence of
food to the chime more viscous that the
drug has to fuse across the chime until it
Biopharmaceutics
Dr. Rana Abu Dahab
Lecture -6- Menas Abu Alhalawa
reaches the surface and get absorbed,
that’s why kind of drug administration in
relation to food is important here two
things must be noted a)safety(when we
have irritant drugs) b)efficacy :rate and
extent of drug absorption , then we balance
between them and decide what is suitable
.
The GI PH : the PH of the fluids vary along
the GIT (1[stomach]7-8[colon])
When it comes to the drug that’s taken
orally we have to remember that it has to
go through all these variations of PH, the GI
PH variability is quite high (some migh have
it as 1 and others as 2.5 and the diurnal
changes between day and night;, it depends
on the general health of the individual ;
emotional status ,stress ,localized disease
situations ,types of food ingested(for
example: spicy food diet leads to a lower
PH) and on anti- cholinergic agents that
influence the PH of the GIT).
PH of the GIT is important for :
1)Dissolution of weak acids and weak bases
2)determining the ratio of ionized and nonionized for the weak acids and weak bases
(remember: the weak bases are solublized
better in the stomach and the weak acids
are solublized better in the intestine)
Another important parameter besides the
PH ; which is according to the PKa of the
drug molecule is the ratio of the non
ionized and the ionized ; whilst the non
ionized are usually more lipophilic so they
cross the membrane easier and here we
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have two opposite functions the first one is
dissolving in the aqueous media so that its
absorbed secondly is the fraction of the non
ionized so that it passes the membranes,
and both of these are influenced by the PH,
which we cannot call it “unpredictable” but
it is highly variable which might be due to
variability of drug absorption (that’s why
sometimes the best absorption can be
sometimes at the initial part of the
duodenum or the last part of it; the surface
are also can affect absorption.
Gastric PH can affect drug absorption in
different ways ; ionization and solubility of
acids and bases and the chemical stability of
drugs in low gastric PH ,and that’s a
problem because most of drugs that aren’t
stable in the stomach are in enteric-coated,
that coat sometimes effects the rate of
absorption of drugs because because the
drug is not emptied from the stomach to
the duodenum until the coat is dissolved so
that the drug is available for absorption.
Other secretions(bile and pancreatic, bile
have PH between 7.8-8.6 concentrated in
the bile , bile has bile salts, bilirobin,
components of hemoglobin, electrolytes,
cholesterol, phospholipids promotes the
dissolution of lipophilic drugs and dosage
forms like the “Grisofulvin”, it improves
membrane permeability; if I had lipophilic
drug and was put with the phospholipids ,
the phospholipids might form micelles and
trap some drug inside and this may
promote drug absorption,,,, or the opposite
formation of insoluble complexes of bile
Biopharmaceutics
Dr. Rana Abu Dahab
Lecture -6- Menas Abu Alhalawa
salts reducing their bioavailability so the
ffect here is negative.
And the last secretions are the pancreatic
secretions, the major component is the
enzymes, they might reduce the
bioavailability of drugs which are made out
of proteins, proteins undergo digestion by
the pancreatic secretions .
Drugs overcome a lot of barriers, and some
drugs even may reach 100% bioavailability!,
to achieve 100% bioavailability by oral route
the drug got to be => *chemically(PH
related) stable in the GIT , they also got to
be stable in the gut lumen (gut lumen
metabolism; whatever secreted in the
lumen drug got to be stable to these lumen
enzymes, we’re mostly talking about
proteolytic enzyme that’d metabolize
proteins, carbohydrates, gluconucleotides
*drug got to be stable to gut wall
metabolism; in gut wall metabolism where
we have 2 factors; 1)brush border enzymes
that are on the surface ,2) and inside of the
cell we have active heterocytes (living) have
sip enzymes, enzymes that drug got to be
stable to these sip enzymes.
Drug moves from lumen trough endothelial
cells, blood vessels, portal circulation then
goes to the liver (hepatic metabolism; first
pass effect which is another challenge for
the drug ,if the drug had lower
bioavailability than 100% by oral route, I’d
give it in higher doses than in IV to
compensate hepatic meatbolism, or we try
to give it IV from the beginning.
Effect of disease status on drug absorption
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(drugs that are taken orally must cross the
GIT; biological variables, gastric emptying
and others, drug has to be stable at the high
PH range and to be stable to secretions,
once drug’s absorbed goes through the first
past effect which afterwards it’d be
available in the systemic circulation (those
are our biological variables determining
drug absorption)
another parameters that could be
determining drug absorption are the
effects of disease status on the drug
availability (Pharmacokinetic studies are
done on healthy humans and it is done by
gathering small group of healthy people and
get them tested for a certain drug effect IV
then Orally administered in order to see
whether the drug is absorbed or not, and
most of the bioequivalence and the studies
that monitor the plasma concentration
time profile are done on young and healthy
individuals, now in reality the patients
aren’t always healthy; taking in
consideration the ones above sixty of them,
the ones that had undergone a certain
surgery or even more, the ones with a
disease or two taking a drug or more then
the medication rate problems might
appear more (effecting the appearance of
drug in circulation and variations in the side
effects)
so keep in mind that there are some
disease conditions do have an effect over
the drug availability
1)Parkinson’s disease : patients have
problems in swallowing dosage forms and
esophageal dismotilitized (motility in the
Biopharmaceutics
Dr. Rana Abu Dahab
Lecture -6- Menas Abu Alhalawa
esophagus is quite slow) so these patients
are unfavorably to be prescribed an oral
dosage forms except for solutions and are
searched for a faster methods to the drug
to reach the stomach (e.g.: using a tube) ,
also all the secretions and the gastric
emptying rate is slower in this disease, if I
wanted the drug dissolution to happen in
the stomach then to get emptied by
reduction of secretions in the stomach
might not be available in the case of this
disease’s condition, so drugs in this case
might be directly administered to the
stomach and won’t fully disintegrate or
dissolve, conc. of solution dosage forms or
liquid dosage forms to account for the
differences in the stomach motility
2) acholrohydric patients (patients with
achlorohydria) ; the acid in the stomach is
surely important for the fluids within the
stomach and the acidic PH is important for
dissolution of weak bases , those patients
have poor acid secretions , the reason could
be parietal cell that secrete the protons, so
we can’t dependent on the acidity of the
stomach to dissolve the drug in this case; as
we’ve been saying that for weak basic drugs
we depend on stomach acidity for an
optimum drug dissolution.
3) congestive heart failure have reduced
splanchnic blood flow ; edema in the bowel
wall – (normal status)one of the most
important variables that allow simple
passive diffusion is the presence of a
concentration gradient ; presence of
mesenteric blood vessels with a very high
capacity that transfers the drug from the GI
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bowl to the portal-circulation to the
systemic circulation,,, patients have a lower
drug absorption because of the
accumulated fluids and then there wouldn’t
be a concentration gradient that’d allow a
rapid simple passive diffusion .
4) inflammatory bowel diseases (in
general) are divided into two subtypes :
Crohn's disease (the inflammatory disease
of the distal small intestine and colon ,
regions of thickening of the bowel wall
overgrowth of bacteria sometimes causes
destruction of the bowel, so the whole area
to which the drug to be absorbed is
deteriorated , so we’d find some areas
where the wall’s thin is where the
absorption is fast and others that are thick
with mucous secretions where absorption is
slowed down (some drugs absorption in this
case is the same, and some are increased or
reduced; mostly this absorption is
unpredictable ) one of the drugs that are
mentioned with Crohn’s disease in which
we have higher plasma concentration in the
case of Crohn’s disease is Propranolol,
which would result in concentration in the
plasma that’s higher ; the first explanation
to that was presence of thin areas that
make absorption faster others say that
because it’s an inflammatory disease so as
an inflammatory disease it’d increase the
plasma protein ; such as specific α-1
glycosidic protein that increases in the
inflammatory situations which the
propanolol binds to and when it does it’s
elimination is reduced and the plasma levels
that are persistently higher in theses
patients.
Biopharmaceutics
Dr. Rana Abu Dahab
Lecture -6- Menas Abu Alhalawa
and Celiac disease : inflammatory disease
effecting mostly the proximal small
intestine (example on sucha disease is the
sensitivity to gluten that causes
inflammation in the small intestines ; the
material in cereals, those patients are
known for their increased gastric emptying
time increased and permeability’s usually
increased resulting in a higher drug
absorption , those patients must be
monitored (for effects and side effects) and
doses should be adjusted ; their plasma
concentration and their drug dosages.
one of the popular cases is the intestinal
infections (usually cause diarrhea which
during it the content residency is lower
than usual) then I’d suspect the drug
absorption to be incomplete ,,,,,oral
contraceptives which are 99.999% effective
in contraception aren’t recommended to be
used during diarrhea because the drug then
won’t be fully absorbed and then the
plasma level of estrogen will reduce again
and there might be a possible ovulation , so
contraceptives are pretty effective unless
there was a case of diarrhea.
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