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15th
World Congress Clinical Nutrition
19th
– 22nd September 2010 El Sokhna Resort - Egypt
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Copyright © 2010.
WCCN2010.COM
All rights reserved |
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Oral – 02 –
David H Alpers
Vitamins as drugs: The importance of pharmacokinetics in oral dosing
David H Alpers, Washington University School of Medicine, St Louis, MO 63130
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Objective: The
principles of PK modeling and tissue
delivery as they apply to vitamins
will be reviewed. These concepts
include loss by first pass
metabolism, tissue
compartmentalization, plasma
clearance, and enterohepatic
circulation. Vitamin D: Vitamin D
undergoes first pass metabolism and
conversion to 25OH vitamin D. It is
also produced from skin at varying
rates. As a result, the serum levels
of 25OHD are quite variable after
oral dosing. In addition, there is
no agreed upon effective level of
25(OH)D for bone health. There are
many vitamin D target tissues in the
body, but the half life (t/2) of the
parent vitamin is short. 25(OH)D
binds tightly to intracellular
vitamin D binding protein (DBP), and
thus has a T/2 of ~15 days. The
active hormone, 1,25 dihydroxyD
binds less well to DBP and has a
shorter tissue T/2 of 102- h.
Vitamins D2 and D3 are probably
interchangeable in terms of
kinetics. Treatment with vitamin D
needs to include awareness of the
difficulty in predicting serum and
tissue levels of hydroxyl versions
of vitamin D, as these will drive
efficacy.
Folate: Many
factors affect the bioavailability
of folate, and its complex
metabolism occurs in 3 compartments:
hydrolysis in the lumen, storage in
the liver, and intracellular
metabolic conversion. Thus, it takes
6-10 days of oral dosing to reach
steady state.
Vitamin B12: Oral
cobalamin is metabolized in the same
3 compartments as is folate, and
like folate can be used for
treatment of deficiency syndromes.
However, it takes 2-3 months before
steady state levels are reached in
plasma. Because of its complex
metabolism, any form of the vitamin
(cyano-, hydroxyl-, or methyl-) can
be used.
‘Anti-oxidant’ supplements: There
are many factors that cause a
discrepancy between the
epidemiologic data suggesting
benefit for anti-oxidant vitamins
and the intervention trials that
show no benefit. One possible factor
is that the dose provided was not
correct.
Vitamin C: Tissue
(e.g. neutrophil) saturation does
not occur until doses of 100-200
mg/day, and there may be genetic
variability in metabolism or
transport.
Vitamin A: Vitamin
A is absorbed into chylomicrons as
retinyl esters (usually palmitate),
transferred to and stored in the
liver, and transported from there to
extrahepatic tissues via retinol
binding protein. Because of this
complex physiology, plasma
appearance curves fit 3 compartment
models, but reappearance from
tissues requires exchange with a
slowly turning over storage
compartment, probably in stellate
cells. The tissue residence time
varies markedly with vitamin A
status, being very long in the
vitamin A replete state and < 1 hr
in the deficient state. It is not
surprising, therefore, that results
of vitamin A supplementation do not
all agree.
Vitamin E: Vitamin
E has been used in many studies to
detect a difference in mortality
and/or cardiovascular disease, but
the results have been largely
negative, and not affected by higher
doses. However, because of passive
absorption, transport in
lipoproteins and not specific
binding proteins, and complex
interactions with other anti-oxidant
systems, the tissue concentrations
of vitamin E are not well
documented.
Conclusions: Many
vitamins are used to treat chronic
degenerative diseases as well as
deficiency syndromes. In most cases,
however, the correct dose to deliver
saturating tissue concentrations is
not known. In addition, the
absorption and metabolism of most
vitamins is complex. Examples are
provided to illustrate the need for
more careful dose response studies,
as is currently done with drugs.
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