Phar 722 Pharmacy Practice III

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Phar 722Pharmacy Practice III

• Vitamins-
• Riboflavin (B2)
• Spring 2006

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Riboflavin (B2) Study Guide

• The applicable study guide items in the Vitamin
  Introduction
• History
• Structure including commercial forms of the
  vitamin
• Conversion to cofactor forms
• Function of the cofactor including the specific
  types of reactions
• Deficiency condition

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History

• Shortly after the discovery of thiamine from
  yeast concentrates, the presence of a second
  nutritional factor in such materials was
  suggested.
• This second factor also was reported to have a
  pellagra-preventative activity since it
  alleviated a deficiency-induced dermatitis in
  rats.
• It was called Vitamin B2 in England and Vitamin G
  in the United States.

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Chemistry

• Riboflavin has a characteristic flavin ring
  system which gives it a unique spectroscopic and
  instability properties.
• Two commercial forms.
• Riboflavin, itself, is poorly water soluble (1
  gm/10,000 ml).
• Riboflavin phosphates solubility is
• 0.1 gm/ml

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Solubility 1 gm/10,000 ml A commercial form
Solubility 0.1 gm/ml A commercial form
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Riboflavin Uptake and Metabolism

• Because of its poor water soluble, uptake of
  riboflavin is slow since the vitamin should be in
  solution in order to enter the intestinal mucosa
  cell. Therefore, it is recommended that
  supplemental administration of riboflavin be done
  with food in order to delay intestinal emptying.
  
• In the mucosa cell, a flavokinase phosphorylates
  the terminal alcohol with a phosphate from an ATP
  forming riboflavin phosphate.
• The latter, as the sodium salt, also is the water
  soluble (0.1 gm/1 ml) commercial form of the
  vitamin.
• The conversion of riboflavin phosphate (FMN) to
  the more common cofactor, flavin adenine
  dinucleotide (FAD) requires the conversion of ATP
  to AMP and the formation of an anhydride linkage.
  
• The pyrophosphate will be cleaved providing
  enough energy for this synthesis to go to
  completion. While it is not clear, this step
  probably occurs in the tissues requiring FAD.
• While flavin chemistry has been studied
  extensively, there has been little research of
  riboflavin biochemistry.

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Biochemical Functions-1

• Riboflavin, as FMN/FMNH2 or FAD/FADH2, is the
  coenzyme/cofactor of flavin enzymes.
• It is required for many oxidation-reduction
  reactions generally (but not always) of
  carbon-carbon bonds.
• Even though there is no defined deficiency
  syndrome, this vitamin is required for several
  life-supporting oxidation-reduction biochemical
  reactions.
• Some examples are on the next slides.

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Biochemical Functions-2

• Oxidation-reduction of carbon-carbon bonds.

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Biochemical Functions-3
Xanthine Oxidase
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Biochemical Functions-4
Electron (respiratory) transport chain
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Biochemical Functions-5

• Oxidation-Reduction of Thiol-Disulfide Systems
• Examples glutathione reductases and lipoic acid
  in oxidative
• decarboxylations of a- ketoacids
  (pyruvate, a-
• ketoglutarate)

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Biochemical Functions-6

• Monoamine oxidase (MAO)
• Examples Metabolism of dopamine, norepinephrine,
  epinephrine
• and serotonin

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Biochemical Functions-7

• Biochemical Transformations of Other Vitamins
• Folic Acid
• Pyridoxine
• NOTE This illustrates how one vitamin is
  dependent on there being an adequate
  concentration of another vitamin. A deficiency
  of one vitamin may induce a deficiency of another
  vitamin.

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Riboflavin Deficiency

• Ariboflavinosis
• Clinical riboflavin deficiency.
• There is no deficiency syndrome in humans
  associated with this vitamin.
• Usually associated with deficiencies of other B
  vitamins.
• Symptoms
• Sore throat
• Redness and swelling of the lining of the mouth
  and throat
• Cracks or sores on the outside of the lips
  (cheliosis) and at the corners of the mouth
  (angular stomatitis)
• Moist, scaly skin inflammation (seborrheic
  dermatitis)
• Vascularization of the cornea
• There is no good assay that correlates a
  riboflavin deficiency with specific biochemical
  function.
• It appears that humans do store appreciable
  amounts (possibly over six months) of the vitamin.

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Hypervitaminosis Riboflavin

• Because of its poor solubility, it probably would
  be difficult to obtain a toxic dose of this
  vitamin.
• Water soluble riboflavin phosphate may be another
  matter. Nevertheless, no significant toxicities
  have been reported.
• Estimated toxic dose 1,000 mg (1 gm)
• There is no UL.

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Dosage Forms

• Most of the commercial forms of the vitamin are
  synthetic.
• Stability
• Riboflavin is one of the most unstable of the
  vitamins, particularly in light. Solutions of the
  vitamin must be protected from light.
• Riboflavin
• This is a neutral molecule. Salt formation is
  not possible.
• Because of its poor water solubility, it is used
  in dry dosage forms.
• Riboflavin Phosphate
• The sodium salt is very soluble (0.1 gm/1 ml).
• It is used in liquid dosage forms.

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DRIs-1

• AI
• Infants 0.3 - 0.4 mg/day
• EAR
• Children (1 - 13 years) 0.4 - 0.8 mg/day
• Males (14 - 19 years) 1.1 mg/day
• Females (14 - 19 years) 0.9 mg/day
• Men (19 - 70 years) 1.1 mg/day
• Women (19 - 70 years) 0.9 mg/day
• Pregnancy 1.2 mg/day
• Lactation 1.3 mg/day

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DRIs-2

• RDA
• Children (1 - 13 years) 0.5 - 0.9 mg/day
• Males (14 - 19 years) 1.3 mg/day
• Females (14 - 19 years) 1.0 mg/day
• Men (19 - 70 years) 1.3 mg/day
• Women (19 - 70 years) 1.1 mg/day
• Pregnancy 1.4 mg/day
• Lactation 1.6 mg/day
• UL
• None reported

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Food Sources

• Liver
• Kidney
• Milk
• Yeast
• Plant
• Animal tissue
• Animals have to obtain riboflavin from plants or
  other animals.