Role of Stomach
End of Section Index
- Stomach Anatomy:
- The stomach is divided into four major regions: fundus, body,
antrum, and pylorus
- Functions:
- reservoir function: achieved through the flexible volume of
the stomach
- emptying function: achieved through low sustained pressure
produced by the stomach body
- mixing and homogenizing function: acheived through stomach
contraction that produces grinding.
- size restriction function: the particle sizes of food emptied
through the pylorus is less than 1 millimeter during the fed state.
- Gastric Mucosa
- The gastric mucosa is mainly lined with epithelial cells,
participating in variety of secretory processes.
- Epithelial Cell Types and Functions:
- Mucous cells secret mucous and
bicarbonate that protect cells against proton.
- Parietal cells produce intrinsic
factor (for B-12 absorption), and secrete proton.
- Peptic cells produces pepsinogen,
which may be activated to pepsin (an protein-degrading enzyme).
- G-cells regulate the production
of gastric juices.
Return to Section Index
A normal adult takes 3-4 kg of food, 5 liters of fluid (including
saliva and gastric juice) per day.
Phases of secretion of digestive juices:
- Cephalic phase (thought of food)
- Sight, smell, and taste of food may induce approximately 1/3
- 1/2 of total secretion (watery mouth, three feet long saliva).
- Ingestion of food and distention of the stomach will induce
remaining secretion (1/2 ~ 2/3)
- Effect of food on secretion
- A increase in food amount increases juices secretion.
- A increase in protein content of the meal also increases secretion.
- Food also affects the gastric pH, although the effect is generally
transient.
Gastric secretion will influence the performance of dosage forms
that depend on gastric juices for dissolution. These dosage forms
include solid dosage forms (e.g. tablet), oral suspension, and
oral solution that have high concentration of solubility-rendering
solvent (e.g., alcohol). This is because solubility-enhancing
solvent (e.g.,alcohol) may be diluted in the presence of food
content, which may result in the precipitation of the drug solids.
Therefore, it is important to take solid dosage forms with appropriate
amounts of water. Although taking water with the dosage forms
is preferred, taking water right after the dosage forms will generally
achieve the same result. At present, patients are often told to
take certain medications with large amount of water. But pharmacists
do not always explain to patients why they recommend it. By the
way, there are other reasons why water should be taken with certain
medications, including producing more urinary flow to reduce the
chance of forming kidney stones.
Stomach has its own motility pattern that are dependent on the
presence of food stuffs. If we focus our own emphasis on aspects
of stomach motility pattern that affect absorption, the main interest
is the residence time of the dosage form in the stomach.
- Fasted Pattern of Motility
- The motility pattern (i.e., interdigestive myoelectric cycle,
or migrating myoelectric complex (MMC)) of the stomach has four
different phases. Each phase lasts for a different period of time
and possesses different contraction strength. The following is
a schematic representation of four contraction phases. Phase I
lasts for 40-60 min with rare contractions. Phase II lasts for
a similar period of time with increasing contraction strength
and frequency (up to 40 millimeter Hg). Phase III lasts for 4-6
min with the highest contraction strength (up to 80 millimeterHg),
which is necessary to empty large indigestible particles (e.g.,
en enteric-coated tablet) from the stomach. Phase IV is a transition
period between phase III and phase III, typically last for 15-30
min. The whole cycle is repeated approximately every 2 hours until
a formal meal time.
- The motility pattern of the stomach during fed state is completely
different that at the fasted state. There are no distinctive phases.
The contraction has moderate strength in the range of 15-20 millimeterHg.
There are two types of contraction: peristaltic contraction and
cystolic contraction. These two contraction patterns are coordinated
to achieve the diminution of the size of the stomach by mixing
and grinding. The systolic contraction is mainly the result of
circular muscle contraction, whereas the peristaltic contraction
is mainly the result of longitudinal contraction.
Gastric Emptying Process
- Gastric emptying of dosage forms are affected by their design
and by the presence of food stuffs. The intactness of some dosage
forms is very important if it is designed for the controlled release
products. It is also important for the performance of enteric-coated
dosage forms. The following scheme summarize possible drug emptying
modes from the stomach.
Return to Section Index
- Factors affecting fasted state motility (or MMC).
- Definition of the fasted state: Only a small amount of liquid
or semisolid in the stomach.
- Osmolarity: An increase in the osmolarity
of the stomach contents decreases gastric emptying rate.
- Temperature: The best is at body temperature. The emptying
rate is slower if cooler or warmer.
- Viscosity: An increase in the viscosity
will decrease the gastric emptying
rate.
- Age: Young people has a faster emptying rate than elderly.
- Dosage form: (will be discussed under "Physicochemical
Factors and Interactions")
- Factors affecting fed state motility.
- Fat: An increase in the fat content decreases the emptying
rate.
- Carbohydrate: An increase in the sugar content decreases the
emptying rate.
- Protein: An increase in
the protein content decreases the emptying rate.
- Amount of food: An increase in the amount of food taken decreases
the emptying rate.
- Physical form: An increase in the solid content of the food
decreases the emptying rate.
- Acidic content: An increase in the acidic
content decreases the emptying rate. This is because acid has
to be neutralized by pancreatic juices, duodenal juices and intestinal
secretion after it is emptied.
- Hormonal factor
- Progesterone increase GI transit time, and decreases esophageal
sphinction tone. This is the main reason some pregnant woman have
higher vomiting potential.
- Posture
- Stomach contents are emptied faster when standing up than
lying down. This posture effect may explain why bed-stricken patients
tend to have poor appetites.
- Dosage form factor (will be discussed under "Physicochemical
Factors and Interactions")
Return to Section Index
Should we take certain
medications with food?
Pros and Cons. Based
on above discussion, it may be advantageous for people to take
certain medicines with food because it may give the drugs more
time to be slowly released into the small intestine. On the other
hand, the onset of action will probably be delayed with food ingestion.
Without Food. For
drugs that are very well absorbed, they are commonly given without
food because there is enough time for them to get absorbed in
the small intestine even if they are emptied as a bolus dose.
For example, a steroid may be absorbed completely regardless of
emptying rate. Drugs that may interact with food should not be
taken with food or milk. These drugs include certain beta-lactam
antibiotics, methyldopa, gebapentin and certain tetracycline analogs
(especially with milk). Drugs should not be taken with food when
a fast onset of action is critical to the patient's well being.
With Food. Some
drugs are taken with food because they cause GI irritations without
food. Other drugs are taken with food because of better absorption
due to improved dissolution characteristics.
Attention. Special
attention is needed when some controlled/delayed release products
are taken because it may have to be treated individually,
Patient Counseling.
Take time to
explain why a medication should be taken with or without a meal
is an important component of patient services the pharmacist is
expected to provide.
Return to Section Index
Intestinal Absorption
- Intestinal Epithelium: The small intestinal epithelium has,
in my opinion, the most awesome superstructure among the human
epithelium. There are three layers of superstructures: Kerckring
folds, villi, and microvilli. As the result of these three structures,
the small intestine has an enormous surface area of 100 square
meters, which is more than 1800 times larger than the monitor
screen you are looking at (assuming a 15 inch monitor).
- Blood Supply
- Blood supply to intestinal mesentery vessels are plenty with
approximately 10% of cardiac output.
- Meal and presence of food in the gut will increase blood supply
to the intestinal mesentery vessels.
- Mesentery vessels collect blood, which eventually go to the
portal vein at a rate of 500 milliliter/min.
- Lymph Supply
- Lymph flow, at a rate of 1-2 milliliter/min, is much smaller
than the blood flow. It is only 0.2 ~ 0.4 % of blood flow rate.
However, the walls of lymph vessel may be quite leaky and allow
the passage of properly assembled fat particles (chylomicrons).
Return to Section Index
a. Intestinal Origin
- Brunner's Glands: These glands are only present in the duodenum.
They secrete bicarbonate and mucus.
- Goblet Cells: These cells secret mucus and enzymes.
- Epithelial Cells: The cells express apically located P-glycoprotein,
which actively pumps out lipophilic xenobiotics including drugs.
b. Pancreatic Origin
- One liter juice/day
- Alkaline
- Enzymes - pancreatic amylase
- Increases in fat and protein contents of the food will result
in more pancreatic secretion.
c. Biliary Secretion
- Bile is produced in the liver. Its main active ingredient
is bile acid, a biological surfactant.
- Functions of bile:
- Emulsification of the fat to form fat-containing micells.
- Absorption of griseofulvin (antifungal) may be enhanced by
ingesting it with a high fat diet.
d. Intestinal pH
- Intestinal pH increases gradually as we move further away
from the stomach. The duodenal pH is quiet low at the duodenal-stomach
junction. Pancreatic and duodenal juices are important source
of alkaline solution that rapidly neutralize acid coming from
the stomach.
- Duodenum (pH3.5-5.5) < Jejunum (pH6.5-7.0) /Ileum (pH7.0-7.5
) < Large Intestine Colon (pH7.5-8.0)
- The pH is going to affect the absorption of weak acids and
bases in the intestine, because it changes the ratio of ionized
versus unionized form.
Return to Section Index
Intestinal motility is a continuation of the gastric motility,
and display motility patterns similar to gastric motility. The
main difference is that the whole stomach is always in the same
phase, whereas different segments of the intestine may be in different
phases. Gastric contraction in the fasted state also tends to
be stronger than that of the small intestine.
- Fasted Pattern:
- Each motility cycle takes approximately 140-150 min to complete,
which is similar to gastric motility under fasted condition.
- Phase I - Basal activity
- Phase II- Random activity
- Phase III - Intense contraction that moves large inabsorbable
substance to large intestine. One contraction starts at the duodenum
stops, whereas the another starts at ileocolonic junction.
- Phase IV - Transition between phase III and I.
- Fed Pattern
- Contraction serves to mix food and promote contact between
food ingredients and the absorption surface.
- An increase in the solid food content of a meal tends to increase
the number of contractions.
- An increase in the carbohydrates also may increase the number
of contractions.
- Ileocolonic Junction
- Functions:
- Food Mixing
- Prevention of bacteria from entering the small intestine.
- Stagnation to allow longer residence time of food ingredients
in the small intestine.
- Transit (residence) time
- Transit time of the small intestine is difficult to change.
- We will discuss later on what can be done to increase the
transit time of dosage forms.
Return to Section Index
- Digestion and Absorption of Nutrients
| Carbohydrates | Digestive Enzymes
| Absorption |
Polysaccharides |
salivary/pancreatic amylase
|
none |
| Oligosaccharides | sucrase, maltase, and lactase
| minimal |
| Monosaccharides | n/a | absorbed
|
| | |
| Protein/Amino Acids (A.A.) | Digestive Enzymes
| Absorption |
Proteins |
pancreatic proteinases
|
minimal |
| Polypeptides | pancreatic and brush peptidases
| minimal |
| Oligopeptides (<4 A.A.) | brush-border and intracellular peptidases
| absorbed |
| Amino Acids | n/a | absorbed
|
| | |
| Fat/Fatty Acids | Digestive Enzymes
| Absorption |
Triglycerides |
pancreatic lipases
|
none |
| Monoglycerides | lipases |
absorbed and reassembled* |
| Long Chain FA | n/a | absorbed and reassembled*
|
| Glycerol | n/a | absorbed and reassembled*
|
| Short/Medium Chain FA | n/a
| absorbed directly |
| | |
*Monoglycerides and long chain FAs are reassembled into triglycerides,
which are exported from the enterocytes as chylomicrons to lymph
tubes.
- Routes of Drug Absorption
- passive diffusion
- carrier-mediated transport
- paracellular diffusion.
- pinocytosis (phagocytosis)
- persorption
- Solvent Drag
- This is a relatively new concept. Originally proposed in the
late 1980's, it has been proposed to be the main absorption pathway
of certain nutrients and drugs with small molecular weight (e.g.,
glucose).
- The Theory: During the rapid absorption of nutrients such
as glucose, there may exist a transit osmotic pressure difference
with higher osmotic pressure in the serosal side of the intestinal
epithelium. To compensate for this transient difference, the paracellular
junction are "opened" to allow increased water absorption
from the lumen. This increased water absorption induces bulk flow
of water, which in turn produces paracellular absorption of drugs
dissolved in water. This solvent drag may affect the absorption
of drug molecules with molecular weight of less than 200.
Return to Section Index
- General Review of Food Effect
- Food Affect:
- Gastric Emptying
- GI Secretion (including pancreatic secretion)
- GI pH
- GI Blood Flow
- Documented Examples of Food Effects
- Food (especially high fat diet) that increases the bile acid
production. For drugs that are poorly soluble, food may be necessary
for optimal absorption.
- Examples:
- Absorption of griseofulvin are significantly higher in the
presence of high-fat diet.
- Isotretinoin is absorbed better if taken 1 hr after meal than
taken without a meal. (Isotretinoin is used to treat severe recalcitrant
& cystic acne)
- Food that affect presystemic blood flow.
- Liver blood perfusion rate without food is normally 500 milliliter/min.
- Liver blood perfusion rate with food may go to 670 milliliter/min
(a 37% increase).
- Propranolol metabolism. First-pass metabolism of propranolol
is decreased when the drug is taken with food, because of saturation
of liver blood clearance (maximum clearance of 500 milliliter/min).
- Food and absorption of drugs with "absorption window."
- "Absorption window" means that drugs are only absorbed
from a particular part of the intestine.
- Riboflavin is absorbed by a specific carrier, its absorption
only occurs at the upper part of the small intestine. Therefore,
slower emptying increases absorption (bioavailability).
- Food components that Chelate with drugs
- Certain inorganic (heavy) metal ions (Ca++
, Mg++) may interact with
certain drugs (e.g., tetracyclines) to form complexation products.
Avoid milk when taking tetracycline and analogs.
- Food components that bind to drugs
- Drug's SH functional group (R - SH) may bind with SH of protein
to form R - S - S - protein, which is too large to absorb intact.
- Captopril and penicillamine are two good examples that this
binding phenomenon may affect their absorption.
Return to Section Index
Return to Section Index
- Importance of Intestinal Metabolism
- Intestinal metabolism of drugs is not generally recognized.
Because FDA does not require drug companies to determine the presence
or absence of intestinal metabolism, the manufacturer typically
attributes drug metabolism to liver. The latter practice is probably
correct most of the time, but there are notable exceptions. For
example, cyclosporin has been found to be extensively metabolized
(up to 35%) by patients who temporarily lost the service of their
liver during the transplant operation (Kolars et al, Lancet, 338,
1488-90, 1991). Other drugs have also been found to be metabolized
in the human intestine (See Table below).
Table: Examples of Drugs Metabolized in the Intestinal Mucosa
(Click here
for a more completed list of drugs metabolized by cytochrome P-450
enzymes)
| Drugs | Enzymes
| Pharmacological Class |
Acetylaminophen |
Sulphotransferase
|
NSAID |
| Aspirin | Esterases | NSAID
|
| Alcohol | Alcohol dehydrogenase
| Potential for Substance Abuse |
| Clofibrate | Esterases |
Hyperlipidemia (Type III) |
| Cyclosporin | P4503A | Immunosuppressant
|
| Despiramine | N-sulphotransferase
| Antidepressant |
| Ethyinylestradiol | P450 |
Female hormone |
| Flurazepam | P450 | Sedative/Hypnotics
|
| Isoniazid | Acetyltransferase
| Anti-TB |
| Morphine | Glucuronosyltransferase
| Analgesics/drug abuse |
| Sulphonamides | Acetyltransferase
| Antibiotic |
| Testesterone | Glucuronosyltransferase
| Male hormone |
| | |
- Intestinal metabolism is an important component of first-pass metabolism .
The latter is important not only for the systemic availability
of drugs, but also for the localized detoxification of drugs and
toxic chemicals. Because the intestinal epithelial cells are loaded
with glutathione-S-transferase and turn over significantly faster
than colon cells, there are very few cases of the small intestine
cancer. This remarkable lack of cancer is achieved even though
the concentration of toxic chemicals is likely to be much higher
in the small intestine than that in the large intestine and colon.
Return to Metabolism Index
- Types of Intestinal Metabolism (Krishna
and Klotz, Clin. Pharmacokinet, 26, 144-160, 1994)
- Phase I Enzymes:
Hydrolysis and Oxidation
- P-450: main isoforms for drug metabolism: 3A4, 2D6, 2C8
- Epoxide Hydrolases
- Hydrolyzing Enzymes
- Phase II Enzymes:
Conjugation (makes drugs more hydrophilic)
- Glutathione S-transferases (GST), including GSTa,
GSTm, GSTp.
Among these isoforms, GSTp
is more abundant in the intestine than in the liver.
- UDP-Glucuronolyltransferases
- Sulphotransferases (ST): phenol (P-ST), and amino (N-ST)
- Acetyltransferases
- Methyltransferases
- Amino acid conjugation enzymes: N-acetyl-CoA synthase
- N-acetyltransferase
- P-Glycoprotein:
Elimination of lipophilic substances
- This is a (mdr1 gene encoded) transporter that acts as a extraction
and/or excretion pump.
Return to Metabolism Index
- Distribution Pattern of Intestinal
Enzymes
- Site-specific distribution
- P4503A4, which is the main constitutive P450 enzyme in the
gut, has its highest activities in the duodenum, followed by the
jejunum and ileum. The enzyme activity in the colon is the lowest.
- Prolidase, which is a cytosolic enzyme that hydrolyzes dipeptides
with an X-Pro (X= any amino acid) designation, appears to have
its highest activity in the jejunum, followed by the duodenum
and ileum. The activity of this enzyme is also lowest in the colon.
- Differentiation-dependent distribution
- Activities of gut enzymes are generally much higher in the
villus tip than in the crypt. The increased metabolic capability
as a function of differentiation is coupled with increased capability
of transport, especially the carrier-mediated transport.
- Diet effects on enzyme distribution
- In general, the diet causes an upper regulation (or enhanced
functional expression) of the metabolic enzymes. In addition,
the site-dependent distribution pattern may change as a result
of fasting. For example, during fasting the overall activity of
the jejunal prolidase activity decreased much more than the activities
of the same enzyme at the other sites.
- Figure Distribution patterns of prolidase along the
intestine. Each segment represents approximately 10 cm of intestine.
Segment #1 is duodenum, #4 jejunum, #8 terminal ileum, #9 large
intestine aboral and immediately adjacent to the ileocaecal junction.
The enzyme was prepared according to methods described under "Research
Design and Methods." Prolidase activity was determined at
37°C using 50 micromolar
Phe-Pro as substrate. Each data point is the average of three
determination, and the error bar is standard deviation of the
mean. The prolidase preparations were pooled from three rats.
- In addition to the general effects of food intake, certain
specific food ingredients may contain chemicals that directly
interact with the metabolic enzymes. For example, some vegetables
(e.g., broccoli) appears to boost the level of glutathione. In
another example, grapefruit juice is known to interact with P4503A4.
The main chemical responsible for this interaction may be naringin
and analogs, although all the chemicals involved have not been
isolated.
- There is generally very little information
available as far as the effect of diet on drug metabolism is concerned.
This is because of the lack of funding that supports this very
important and practical aspect of drug metabolism. I believe this
problem is going to get worse because diversity of demography
means more food ingredients will be introduced into general consumption.
Pay special attention to your continuation education materials
and trade journals for alerts about nutrient-drug interactions.
Return to Metabolism Index
- Saturation of Intestinal/Hepatic Drug Metabolism.
- The percent of absorption of certain drugs, which are eliminated
by metabolism, may rise as the result of a dose increase because
of metabolism saturation. For example, bioavailability (or percent
of the intact drug reaching the systemic circulation) of nicardipine
(a calcium channel blocker) was shown to increase with dose (Kelly
and O'Malley, Clin. Pharmacokin., 22, 416-433, 1992). This hypotheses
can be tested using a potent P4503A4 inhibitor like ketoconazole.
If the reason is indeed metabolism saturation via P4503A4, then
a combination of ketoconazole and nicardipine will raise the bioavailability
of nicardipine as well.
- Saturation of Intestinal P-Glycoprotein.
- The percent of absorption of certain drugs, which are mainly
eliminated intact, may be increased when the drug dose was increased.
For example, the percent of absorption of celiprolol, which is
a newer generation of cardiac b-blocker
was shown to increase with the dose (Kuo et al, Pharm. Res., 11,
648-653, 1994). This hypothesis can be tested by using specific
inhibitors of p-glycoprotein (e.g., verapamil). If the reason
is not p-glycoprotein, a combination of verapamil and celiprolol
should not increase celiprolol's % absorption.
- Drug-Drug and Drug-Nutrient Interactions.
- Cyclosporin, an immunosupressant for organ transplants, is
significantly metabolized by the small intestine. By testing whether
a coadministered drug may interact with cyclosporin, it is possible
to determine whether the % absorption will change with dual drug
combinations with in vitro experiments. This type of study is
important because a wide array of drugs may interact with cyclosporin
absorption, including calcium channel blockers (e.g., nifedipine),
macrolide antibiotics (e.g., erythromycin), and cholesterol lowering
drugs (e.g., lovastatin).
- Grapefruit juice has been shown to significantly improve the
bioavailability of several calcium channel blockers, including
felodipine and nifedipine (Bailey et al, Clin. Pharmacokin. 26,
91-98, 1994). For example, felodipine bioavailability was increased
by as much as 383% in certain patients when the drug is taken
with the grapefruit juice (Bailey et al, Clin. Pharmacokin. 26,
91-98, 1994). This effect of the grapefruit juice is mainly attributable
to one active ingredient, naringin and its analog naringenin (Bailey
et al, Clin. Pharmacokin. 26, 91-98, 1994). Absorption of other
drugs that are metabolized by P4503A4 (also called CYP3A4) may
also be affected by the grapefruit juice. A case and an example
is cyclosporin.
Return to Metabolism Index
Return to Section Index
Which Juice Did You Have?
On a beautiful Saturday afternoon, Vivian
Lee, a transplant pharmacist at Mystic Memorial Hospital in Spokane,
Washington, was awoke from a sun-bath session at a local hide-out
by a paging beep. Who would bring this stuff here and how come
it is not going away? Then she suddenly realized that she is on
call today. She reached over to her bag, took out a cellular phone
and called. Dr. Allan Smith was on the other side. "Vivian,
Mr. Jones started to show signs of serious cyclosporin-related
kidney toxicity," he said. "Really?! But he was doing
really well a week ago when he left for home. Where is he?"
"He is in the emergency room. Could you come?" said
Allan. "I'll be on my way."
On her way to the hospital, Vivian started
to replay the patient counseling session she had with Mr. Jones.
She remembered that she has to reduce Mr. Jones dose of cyclosporin
because he appeared to have higher plasma concentration than average.
I hope he did not overdose himself, Vivian said to herself. Besides
that, she could not think of anything she have not told him. Upon
arriving at the hospital, she rushed into the Emergency room and
started to look at the Mr. Jones' case history and recommend the
appropriate pharmaceutical care. Because she could not find anything
unusual in the history and there is no sign that Mr. Jones overdose
himself, Vivian decided to wait until Mr. Jones gets better.
On Wednesday, Vivian went back to check
with Mr. Jones. She entered room and greeted Mr. and Mrs. Jones.
"Good Morning! Mr. Jones. It is so nice to have you feeling
much better again." "Thank you, Dr. Lee." "I
would like to find out why there was this severe adverse reaction
so that it will not happen again," said Vivian, "and
I will need your help on how you have used the prescribed medication."
"How many times did you take cyclosporin
per day?" asked Vivian. "Two." Did you go to other
doctors and get new prescriptions?" "No." "Did
you take any OTC products?" "Yes, I took Tynolol®
for headache." "What did you eat regularly?" "Cereal,
juices, milk, beef, green leaf vegetable, and potato." "Which
juice?" "Grapefruit for breakfast, apple for lunch,
and a juice cocktail for dinner." "What is the name
and brand of the juice cocktail? "Welch's Orchard Fruit Juice
Cocktail"." Based on the information provided to Vivian,
she was able to advise Mr. Jones what to take with the medicine
and what to avoid.
Questions:
1. What do you think Vivian has told Mr.
Jones to avoid and why?
2. Would a change in the drug formulation
help alleviate the problem?
3. What would be the consequence of taking
cyclosporin with felodipine?
4. Why is it necessary to convince the patient
that he needs to be careful about his selection of juices? List
brands of juices he may or may not use. Be specific and explain.
Click here for the key
to a straight-forward answer.
Drugs are considered to be bioavailable only after
it has reached the systemic circulation, although there are notable
exceptions with locally active drugs (e.g., topical creams). Although
this rule is not perfect, it is generally accepted by the Food
and Drug Administration (http://www.fda.gov) as the gold standard
in the evaluation of dosage form performance.
First pass metabolism refers to a set of events that
decrease the systemic availability of drugs after they are absorbed.
The events include: intestinal excretion via p-glycoprotein,
intestinal metabolism via various phase I and phase II enzymes,
hepatic excretion via bile, and hepatic metabolism via various
phase I and phase II enzymes.
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Phase I metabolic enzymes catalyze biological reactions
that break up a labile covalent bound, and/or add a -OH group
to a electron-rich functional group.
Typical phase I enzymes are hydrolyases and oxidases
including:
- Cytochrome P-450 (CYP). In humans, the main CYP
isoforms include 3A4, 2D6 and 2C8. CYP is the most important class
of enzymes for drug metabolism. CYP catalyzes oxidative metabolism
of most lipophilic drugs to metabolites that are typically further
metabolized via phase II enzymes to form hydrophilic substances.
Hydrophilic substances can then be eliminated relatively easily
from the body.
- Epoxide Hydrolases. The microsomal epoxide hydrolases
is a class of detoxification enzymes working closely with CYP.
Significant cell damage may occur without these enzymes. Hence,
they are a necessary component in the metabolic inactivation of
enzymes.
- Hydrolyzing Enzymes. These enzymes include proteases,
esterases, amidases, peptidases, lipases, and polysaccharidases.
Many hydrolyases are pharmacologically important. For examples,
gut peptidases prevent the oral delivery of many highly active
peptides, and esterases are often used to convert prodrugs into
their active therapeutic parent agents.
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Phase II metabolic enzymes catalyze biological reactions
that attach a hydrophilic groups to drugs or their metabolites.
The resulting metabolites are typically much more water-soluble
and may be easily eliminated via urine or bile or both.
Typical phase II enzymes are transferases and synthases
including:
- Glutathione S-transferases (GST), including enzyme
isoforms GSTa,
GSTm, GSTp.
GSTp is
more abundant in the intestine than in the liver. This enzyme
catalyzes the conjugated reaction of an electrophilic metabolite
with a tripeptide glutathione. It represents a major detoxification
pathways for drugs and carcinogens.
- UDP-Glucuronosyltransferases. This microsomal
enzyme is quantitatively the most important phase II conjugation
enzymes. It attaches a glucuronic acid to a variety of functional
groups (e.g., -OH, -COOH, -NH2, -SH) to form N-, S-,
O-glucuronide conjugates. The resulting conjugates are typically
hydrophilic, which facilitate their elimination via urine and/or
bile.
- Sulfotransferases (ST): phenol sulfotransfereases
(P-ST), and amino sulfotransfereases (N-ST). These enzymes catalyze
the transfer of inorganic sulfur (typically -SO4) to
drugs and make the metabolites more water soluble.
- N-acetyltransferases. Only phase II reaction
that makes the metabolites less hydrophilic. The resulting acetylated
metabolite may have a longer half-life than the compound before
acetylation.
- Methyltransferases and amino acid conjugation
enzymes (e.g. N-acetyl-CoA synthase). These enzymes are less important
for drug metabolism than those described above. Their main function
is to participate in the metabolism of endogenous substances (e.g.,
DNA and protein metabolism).
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P-Glycoprotein serves as a first-line defense against
accidental ingestion of toxic substances. First identified in
multidrug-resistance cancer cells, p-glycoprotein was also found
in normal human tissues including the intestine. The primary function
of p-glycoprotein is to pump out its substrates (typically cytotoxic
agents) from within the intracellular domain.
In the small intestinal cells, p-glycoprotein can
pump drugs out of the intestinal cells after they have penetrated
the apically located lipid bilayer. They represent a significant
mechanism of intestinal excretion for certain drugs (e.g., celiprolol).
In patients suffering from cancer, the ability of
the cancer cells to develop resistance to drugs with different
chemical structures remains a serious challenge to the cure of
cancer.
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1. Dr. Lee told her patient that scientists
had found recently that certain chemicals in the grape fruit juice
may interact with drug metabolic enzymes including cytochrome
p-450 which metabolizes cyclosporin. She advise patient not to
take cyclosporin with the grapefruit juice because it may elevate
the systemic cyclosporin level.
2. A change in drug formulation is not a
viable solution to the problem because a formulation that has
better bioavailability will result in more severe side effects,
while a formulation of a lower bioavailability is likely to cause
more inconsistency and waste.
3. Taking drugs that will interfere with
the metabolism of cyclosporin will also cause severe side effects
and should not be taken with cyclosporin. Therefore, felodipine
or other drugs that interfere with cytochrome p-450IIIA enzymes
should not be taken with cyclosporin.
Brief Summary of Long Term (quality solution)
1. Advise patient to avoid any juice that
contains grape fruit juice such as Welch's Orchard Fruit Juice
Cocktail. Better yet, direct patient to take only certain types
of juice and avoid others, especially in elderly patients. Continue
to track literature on the report of similar incidence of food-drug
interactions. This problem will probably become worse because
a diverse culture will consume a diverse food, which may result
in problem yet to be identified.
2. Continue to track drug-drug interactions
and be aware of patients taking medicine prescribed by different
doctors and filled by different pharmacists. Continue to track
research report on the possible drug-drug interactions both at
the absorption and metabolism levels.
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