Phar 722Pharmacy Practice III

Vitamins-

Pyridoxine (B6)

Spring 2006

Pyridoxine Study Guide• The applicable study guide items in the

Vitamin Introduction• History• Nomenclature• Structures of the vitamins and conversion to

the cofactor forms• Functions of the cofactor forms including the

specific types of reactions• Deficiency conditions• Drug-vitamin interactions• Dietary and commercial forms of the vitamin

History

• First isolated in 1934 as a factor responsible for curing a type of rat dermatitis. – Much recent research has been conducted at

Oregon State University.• There is no historical “disease” associated

with this vitamin.• The “importance” of this vitamin was

discovered when an infant milk formulation was sold without pyridoxine. – The infants developed convulsions and there

were deaths.– Initially, there was confusion as to whether there

was a contaminant in the milk.

Chemistry• There are three forms of the vitamin.

– Pyridoxine is found in plants.• Common commercial form.

– Pyridoxal found in animals.• Never commercial.

– Pyridoxamine found in animals. • Not found in common vitamin preparations.

• The forms found in animals came from eating vegetable sources or other animals.

Pyridoxine Uptake and Metabolism

• All three forms are absorbed from the intestine and transported to the liver where they are phosphorylated.

• All three are interchangeable as their respective phosphate esters.

• Transport throughout the body seems to be on serum albumin.

• Pyridoxal phosphate is considered the cofactor form of the vitamin.

ADP

ATP

NH3C

HO

CH2NH3+

CH2OH

NH3C

HO

CH2NH3+

CH2OP

FMNFMNH2

FMNFMNH2

FADH2

ADP

ATP

FAD

NH3C

HO

CHO

CH2OH

NH3C

HO

COO-

CH2OH

NH3C

HO

CHO

CH2OPFMNH2

NAD+

FMN

ADP

ATP

NH3C

HO

CH2OH

CH2OH

NH3C

HO

CH2OH

CH2OP

4-Pyridoxic Acid(metabolite)

Pyridoxal

Pyridoxal P(coenzyme/cofactor)

Pyridoxamine P

Pyridoxamine(a commerical form)

Pyridoxine(a commercial form)

Pyridoxine P

NADH + H+

Oxidase

Oxidase

Oxidase

Oxidase

Pi

Phosphatase

Pi

Phosphatase

Pi

PhosphataseKinase Kinase Kinase

OxidasePlants Animals

• Transamination: – Nearly every amino acid requires pyridoxal phosphate (PLP)

for its metabolism.

• Decarboxylation of amino acids: – DOPA to dopamine; – Histidine to histamine; – 5-OH-Tryptophan to serotonin

• Production of glucose-1-P from glycogen.

• Conversion of homocysteine to cysteine and glycogenic end products.

• Other reactions where an amine moiety is part of the reaction scheme.

Biochemical Functions

R C CO2-

H

NH3+

N

CH2OP

H3C

HO

C

O H

H2O

N

CH2OP

H3C

HO

CH

NH+

CR CO2-

H

N

CH2OP

H3C

HO

CH2

NH+

CR CO2-

H2O

CO2

N

CH2OP

H3C

HO

CH

NH+

CR

H

H

H+

H2O

R H

NH3+

H

O

CR CO2-

N

CH2OP

H3C

HO

CH2

NH3+

+

Aldimine

Amine

Pyridoxal P

-amino acid -keto acid

+

Pyridoxamine P

N

CH2OP

H3C

HO

CH2

NH+

CR' CO2-

R' C CO2-

O

R C CO2-

O

H2O

R' C CO2-

H

NH3+

-amino acid

Deamination

TransaminationDecarboxylation

N

CH2OP

H3C

HO

C

O H

Pyridoxal P

Pyridoxine deficiency-1• Deficiencies are seen with this vitamin.

– In infants there is a characteristic type of convulsions which is reversible when pyridoxine supplements are given.

– Deficient infants also show a characteristic electrical encephalogram. (This was "discovered" when infants were fed an infant formula lacking pyridoxine.)

• Pyridoxine has shown no beneficial results for adults with convulsive disorders.

• The neuropathies seen in pyridoxine deficiencies probably relate to its requirement for the biosynthesis of three neurotransmitters – serotonin from tryptophan and norepinephrine and epinephrine from L-DOPA (Dihdroxyphenylalanine). L-DOPA is formed from tyrosine by DOPA decarboxylase, a pyridoxal P containing enzyme.

Pyridoxine deficiency-2• Considering the central role that this vitamin plays in amino acid

metabolism, it is a wonder that there aren't more visible signs of this deficiency.

• A change in the glucose tolerance curve has been reported in pyridoxine deficient subjects.

• Elevated homocysteine may indicate a pyridoxine deficiency, but it also can indicate problems with folic acid and cobalamin status.

• There have been reports that pyridoxine supplements might be beneficial for neuropathies, particularly those that are drug-induced, and carpal tunnel syndrome.

• Proof of its role in treating depression and carpal tunnel syndrome is equivocal.

• Because it is required in the conversion of tryptophan to niacin, pyridoxine may have a niacin-sparing effect.

Drug – Vitamin Interactions-1• Isoniazid (INH)

– The widely used antitubercular drug isoniazid, INH, can induce a pyridoxine deficiency.

• A peripheral neuritis develops. • This interaction has no relationship to INH's antitubercular

activity. – Therefore, pyridoxine supplements do not require altering INH

dosing schedules.

• Penicillamine– This drug is a copper chelator used in Wilson’s Disease

(copper storage disease) and has two amine groups.

• There may have been an interaction of some type with the earlier high dosage oral contraceptives.– This was based on a tryptophan load test.

N

C

OHN

NH2

N

CH2OPHO

H3C

O H

N

C

OHN

N

Isoniazid (INH)Isonicotinic Acid Hydrazide

+

Pyridoxal P

H

N

CH2OP

HO

H3C

H2O

Isoniazid Pyridoxal Adduct

Drug – Vitamin Interactions-2

• L-DOPA– Parkinsonian patients taking L-DOPA must

restrict their use of pyridoxine containing vitamin supplements to formulations containing only the adult RDA.

– Excessive amounts of pyridoxine will cause peripheral decarboxylation of L-DOPA (from DOPA decarboxylase in the mucosa) producing dopamine.

• This reduces the amount of L-DOPA that will cross the blood brain barrier.

Hypervitaminosis Pyridoxine• A certain mystique has built up around this vitamin

resulting in individuals overdosing themselves. • Most of this “mystique” focuses on the role of

pyridoxal P in the conversion of glycogen to glucose-1-P. – Example: Marathon runners take pyridoxine for the final “boost” to finish the race.

• Serious neurological problems have been seen in doses of 1 - 6 gm/day for 2 - 40 months.

• Megadosing below 2 gm/day seem safe, but all of this information is based mostly on anecdotal reports.

• There is an UL for this vitamin, considerably below the 2 gm/day.

Dosage Forms

• Commercial Form:– Synthetic pyridoxine

DRIs-1• AI

– Infants (0 - 12 months) 0.1 - 0.3 mg/day (≈0.014 mg/kg to ≈0.033 mg/kg)

• EAR– Children (1 - 13 years) 0.4 - 0.8 mg/day– Males (14 - 19 years) 1.1 mg/day– Females (14 - 19 years) 1.0 mg/day– Men (19 - 50 years) 1.1 mg/day– Men (51+ years) 1.4 mg/day– Women (19 - 50 years) 1.1 mg/day– Women (51+ years) 1.3 mg/day– Pregnancy 1.6 mg/day– Lactation 1.7 mg/day

DRIs-2• RDA

– Children (1 - 13 years) 0.5 - 1.0 mg/day– Males (14 - 19 years) 1.3 mg/day– Females (14 - 19 years) 1.2 mg/day– Men (19 - 50 years) 1.3 mg/day– Men (51+ years) 1.7 mg/day– Women (19 - 50 years) 1.3 mg/day– Women (51+ years) 1.5 mg/day– Pregnancy 1.9 mg/day– Lactation 2.0 mg/day

• UL– Children (1 - 18 years) 30 - 80 mg/day– Adults (19 an older) 100 mg/day

Food Sources• Wheat germ

• Milk

• Legumes

• Meat

• Vegetables

• Dietary forms will be the various cofactor structures.