1. Phar 722 Pharmacy Practice III Vitamins- Biotin Spring 2006

2. Biotin Study Guide The applicable study guide items in the Vitamin Introduction History Structure of the vitamin and cofactor forms Function of the cofactor including specific types of reactions catalyzed Deficiency condition

3. History 1916 –It was recognized that rats fed a diet high in raw egg white exhibited muscle incoordination, dermatitis and loss of hair. Cooked egg white was not toxic. –The toxicities from the raw egg white could be prevented by feeding liver or yeast to the animals. –Deficiencies can be induced by a diet restricted to raw egg white. 1942 –The biotin structure was published.

4. Biotin Chemistry Biotin consists of two 5-membered rings cis- fused to each other. The d-isomer is the only active form.

5. Biotin Uptake and Metabolism Little is known about biotin uptake. There does not seem to be a cofactor form different from the basic structure. The carboxyl chain forms an amide linkage with the ε-amino nitrogen of lysine which binds the vitamin to the enzyme's active site. Biotin is required for the addition of carbon dioxide in many, but not all, carboxylation reactions. There is some debate about the structure of the cofactor intermediate that transfers the carbon dioxide. See the next slide.

7. Addition of CO 2 to biotin for subsequent carboxylation reactions.

8. Biotin Function-1 Methylmalonyl CoA from propionyl CoA

9. Biotin Function-2 Oxalacetate from pyruvate (gluconeogenesis; anapleurotic reactions)

10. Biotin Function-3 Formation of carbamyl phosphate (urea cycle)

11. Biotin Function-4 Malonyl CoA from acetyl CoA (fatty acid synthesis)

12. Biotin Function-5 Metabolism of leucine

13. Biotin Deficiency One of the ways to induce a deficiency in humans is to feed the volunteer a raw egg white diet. –Deficiency symptoms include hair loss, a rash around the nose and mouth, and conjunctivitis. A good source of biotin is egg yolk. –Therefore, eating whole raw eggs will not cause a deficiency of this vitamin (although person could be at increased risk for salmonella poisoning). What is the problem with raw egg white? –Egg white contains a basic protein known as avidin which forms salt linkages with the acidic biotin that might be in the intestinal tract (possibly produced by intestinal bacteria?). This complex is not absorbed, but remains in the intestine eventually to be excreted. –Cooking the egg white ties up the avidin in the rest of the egg albumin preventing its binding biotin.

14. Hypervitaminosis Biotin None has been reported in humans. There is no UL.

15. Dosage Forms The synthetic racemic mixture is used commercially. –As with racemic pantothenic acid and pantothenol, only half of the racemic biotin is active. Biotin is considered one of the more expensive vitamins and can add to the cost of the final product. Solubility 0.3 -0.4 mg/ml (1 gm/2,500-3,300 ml)

16. DRIs AI –Infants5 - 6 μg/day –Children (1 - 13 years)8 - 20 μg/day –Adolescents (14 - 18 years)25 μg/day –Adults30 μg/day –Pregnancy30 μg/day –Lactation35 μg/day EAR –None reported RDA –None reported UL –None reported

17. Sources Liver Kidney Yeast Animal and plant tissue in general; Possibly the intestinal bacteria