Transcript Phar 722 Pharmacy Practice III

Phar 722
Pharmacy Practice III
VitaminsVitamin E Family
Spring 2006
Vitamin E Study Guide
• The applicable study guide items in the
Vitamin Introduction
• History
• Structure of the active and commercial forms
• Transport of the vitamin
• Compare and contrast vitamin deficiencies in
humans relative to animals
• Role of structurely related compounds
• Hypervitaminosis E
• Approaches to formulation
Vitamin E History
• 1922
– Evans and Bishop showed that rats
maintained on certain diets did not
produce offspring.
– These same rats seemed normal in all
other respects including physical growth.
– The condition could be corrected by
addition of lettuce, whole wheat, and
cereal grains.
– Later it was shown that the vitamin activity
was in certain wheat germ oils.
Vitamin E Chemistry-1
• The tocopherols and tocotrienols are natural
antioxidants found in vegetable oils.
– Historically, they were removed during the refining
process.
– Of course this means that the refined products are
subject to oxidative spoilage. Therefore, the
manufacturers add antioxidants back into the
products.
• These may be tocopherols or synthetic compounds.
– Tocopherols are widely used as antioxidants in
prepared foods.
• The milling companies are major suppliers of
tocopherols extracted from the wheat germ.
Vitamin E Chemistry-2
• Tocopherol means child bearing alcohol.
– tokas - child
– phero - to bear
– ol – alcohol
• The chemistry is complex.
– There are a family of tocopherols, with αtocopherol showing the most specific
vitamin activity based on a rat fertility
assay.
– Consensus is developing that vitamin E
should be defined as 4 tocopherols and 4
tocotrienols.
Vitamin E Chemistry-3
• The stereochemistry is very
important!
• There are three chiral centers (position
2 on the chroman ring and positions 4'
and 8' on the phytyl chain. This means
that eight isomers are possible.
– The normal situation seen with vitamins
that have two or more stereoisomers is
only one isomer is active. Thus a racemic
(usually represented as d,l) mixture
contains 50% of the activity compared with
an equi-molar amount of the active isomer.
Vitamin E Uptake
• Bile (conjugated bile salts) is essential for absorption.
• The vitamin usually is present in food or vitamin supplements
as an ester. This is hydrolyzed in the intestinal tract. The free
tocopherol becomes part of the mixed micelles. Absorption is
35-85% efficient.
• Entry into the body is made on the chylomicrons by the
lymphatic system. The vitamin is transported throughout the
body on chylomicrons, VLDL, LDL, and HDL. It is distributed in
adipose tissue, liver and muscle.
– There is evidence that transport across the intestinal mucosa cells
followed by incorporation into chylomicrons may favor RRR αtocopherol because of an α-tocopherol transfer protein.
• The natural RRR isomer is preferred for incorporation into very low
density lipoprotein (VLDL).
• The tocopherols can be considered nature’s oil soluble antioxidant in both plants and animals with animals, including
humans, obtaining the vitamin from plants.
Vitamin E Deficiencies-1
• There has been a considerable mystique that
surrounds this vitamin.
• There doesn't seem to be a defined
deficiency syndrome in humans for which
there is a parallel model in animals.
– To put it another way, there is no valid animal
model that can be extrapolated into humans.
• The next slide shows one classification
system for tocopherol deficiencies.
Vitamin E Deficiencies in
Animals and Humans
• Vitamin E Deficiencies Seen in Animals
– Reversible reproductive failure in the female rat.
– Irreversible degeneration of rat testicular tissue.
– Nutritional muscular dystrophy in monkeys, rabbits,
guinea pigs, lambs, calves, turkeys and chicks.
– Anemia in monkeys.
• Vitamin E deficiency seen in humans (Most reported
deficiencies are caused by problems with fat
absorption.)
– A partially reversible set of neurological problems.
– Hemolytic anemia in premature infants.
Vitamin E Deficiencies-2
•
In summary, there seems to be a general antioxidant role and a
specific function in the cell's oxidation-reduction systems. This may
complement some of the functions attributed to glutathione.
•
There has been considerable debate as to whether the RRR isomer is
the only biologically active form of the vitamin. The synthetic form of
the vitamin is a mixture of all eight stereo isomers (now referred to as
rac-α-tocopherol rather than d,l-α-tocopherol).
– Many of the research articles reporting on the effectiveness of vitamin E
use commercial products which usually have a mixture of isomers and
don’t have any tocotrienols.
•
Recently, there is debate as to whether the α and γ forms have
different in vivo activities.
– γ-Tocopherol is the predominant dietary form.
– But α-tocopherol may displace the γ-isomer.
•
Because there are both general and stereo-specific antioxidant
activities, the RDA tables state that the activity ratio of RRR-αtocopherol to rac-α-tocopherol is 1 to 1.36.
Vitamin E Deficiencies-3
• Complicating these evaluations further
is the observation that an in vitro
comparison of the antioxidant activities
of α-, β-, γ-, and δ-tocopherols is not
parallel with in vivo vitamin results in
rats.
Vitamin E Deficiencies-4
•
•
•
•
The in vivo rat fetal rankings for the tocopherols are:
α>β>γ>δ
Depending on the solvent, the in vitro antioxidant rankings can
parallel the in vivo. When carrying out the evaluation in fats and oils,
the in vitro rankings are:
δ>γ≈β>α
•
All isomers are antioxidants and probably do provide general
antioxidant protection internally or in vivo. On the other hand,
evidence points to the RRR isomer as being specific for a variety of
reductase systems, possibly involving selenium (Se) and glutathione
(GSH/GSSG). The "Relative Biological Activity" in the previous table is
based on a rat resorption-gestation assay.
•
The next two slides illustrate how the tocopherol family might function
as antioxidants.
Possible Vitamin E Antioxidant Mechanism
R1
HO
4
5
CH3
6
7
1
8
R2
H3C
2
H
1'
H
4'
O
H3 C
CH3
H3 C
H
12'
8'
CH3
Reduced Tocopherol (hydroquinone)
[H]
[O]
R1
O
5
4
CH3
6
7
8
R2
1
2
O
H3 C
CH3
H3 C
1'
H
H3C
4'
Oxidized Tocopherol (quinone)
H
8'
H
12'
CH3
Possible Free Radical Antioxidant Mechanism
CH3
CH2
O
5
HO
4
6
7
CH3
5
4
8
1
O
6
8
H3C
1
2
O
H3C
CH3
Chromanoxyl radical
7
Phyt.
H3C
2
O
H3C
CH3
Chromanol methide radical
7
Phyt.
5
4
8
1
H3C
2
O
H3C
CH3
Chromanone-8a radical
Phyt.
Vitamin E Deficiencies-5
• Consistent with antioxidant model, the RDA
is based on the polyunsaturated fatty acid
(PUFA) consumption. The implication is that,
if a increased PUFA intake is recommended,
the RDA for tocopherol should be increased.
• The hemolytic anemia seen in premature
infants is one of the few specific nutritional
deficiencies seen in humans.
– Because of poor placental transfer, newborn have
little of the vitamin. Human milk contains 2 - 5
mg/liter. Cow's milk contains less.
Current Information on Vitamin E
• γ-Tocopherol is the most common form in the U.S. diet, but αtocopherol is the most common form found in the blood.
– In the blood on: lipoproteins (VLDL, LDL, etc.)
– α-Tocopherol may be more effective than γ-tocopherol in protecting
against prostate cancer. This may be more effective in smokers.
– See food lists for distribution of the α and γ forms.
• Some evidence that vitamins C and E, zinc and , but not βcarotene, help patients with early signs of age-related macular
degeneration.
– Current trial involving these nutrients plus selenium underway.
• Meta-analysis show no risk reduction for myocardial infarction,
stoke or cardiovascular death.
• Some studies show increased oxidant activity with doses above
400 IU.
• Vitamin E did not slow the progression of Alzheimer’s Disease.
Hypervitaminosis E
• This is a relatively safe vitamin.
• But toxicities have been reported involving chronic
administration of 300 – 1200 mg per day.
– The symptoms can be very serious and include
thrombophlebitis, pulmonary embolism, hypertension,
breast development in men and children, severe fatigue,
and nonmalignant breast tumors.
• In 2004, there were news reports that high doses
(2000 IU/day) of vitamin E slowed the progression of
Alzheimer’s Disease. What the news failed to report
was that a diet rich in foods containing vitamin E
may help protect some people against Alzheimer’s
Disease.
– There are at least five ongoing studies examining the role of
antioxidants in delaying onset of Alzheimer’s Disease.
Dosage Forms
• Stability
– The tocopherols, being antioxidants, are
very sensitive to oxygen. Sensitive to UV
light is another problem. There are two
provitamin esters that are used
commercially.
• Acetate
– used in oils, emulsions, gelatin matrices, etc
• Hemisuccinate
– Used in dry dosage forms requiring a free flowing
powder. In theory, the sodium salt would be water
soluble enough for aqueous injections.
Vitamin E Dosage Forms
O
H3 C
C
CH3
O
5
4
8
1
CH3
6
7
H3 C
2
H3 C
1'
H
H 3C
4'
O
H 3C
H
H
12'
8'
CH3
CH3
Tocopherol Acetate
O
Na+ -O
C
O
CH2
CH2
C
CH3
O
5
4
8
1
CH3
6
7
H 3C
2
O
H 3C
H3C
1'
H
4'
CH3
Tocopherol Hemisuccinate Sodium Salt
H 3C
H
8'
H
12'
CH3
DRIs (based on α-tocopherol)-1
• AI
– Infants (0 - 12 months)
0.6 mg/kg/day
• EAR
–
–
–
–
–
–
–
–
–
Children (1 - 8 years)
Boys (9 - 18 years)
Girls (9 - 18 years)
Men (19 - 50 years)
Women (19 - 50 years)
Men (51 - 70+ years)
Women (51 - 70+ years)
Pregnancy
Lactation
5 - 6 mg/day
9 - 12 mg/day
9 - 12 mg/day
12 mg/day
12 mg/day
12 mg/day
12 mg/day
12 mg/day
16 mg/day
DRIs (based on α-tocopherol)-2
• RDA
– Children (1 - 8 years)
– Boys (9 - 18 years)
– Girls (9 - 19 years)
– Men (19 - 50 years)
– Women (19 - 50 years)
– Men (51 - 70+ years)
– Women (51 - 70+ years)
– Pregnancy
– Lactation
6 - 7 mg/day
11 - 15 mg/day
11 - 15 mg/day
15 mg/day
15 mg/day
15 mg/day
15 mg/day
15 mg/day
19 mg/day
DRIs (based on α-tocopherol)-3
• UL
– Infants
Not established (Do not give
supplements; use only food and
formula for sources.)
– Children
200 mg/day (1 - 3 years) up to
600 mg/day (9 - 13 years)
– Adolescents
800 mg/day
– Adults (19+ years)
1,000 mg/day
– Pregnancy
800 - 1,000 mg/day
– Lactation
800 - 1,000 mg/day
Food Sources-1
• α-Tocopherol
– Almonds, hazelnuts, sunflower seeds
– Spinach
– Olive oil, canola oil
• γ-Tocopherol
– Soybean oil, corn oil
• Tocotrienols
– bran and germ fractions of certain seeds
and cereals
Food Sources-2