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Fluoride Metabolism

DENT 5302 TOPICS IN DENTAL BIOCHEMISTRY 9 April 2007. Fluoride Metabolism. Objectives:. Metabolic handling of ingested fluoride Absorption, soft-tissue distribution, hard tissue uptake, and excretion. Outline. Overview of fluoride metabolism. Factors affecting fluoride absorption.

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Fluoride Metabolism

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  1. DENT 5302 TOPICS IN DENTAL BIOCHEMISTRY 9 April 2007 Fluoride Metabolism Objectives: • Metabolic handling of ingested fluoride • Absorption, soft-tissue distribution,hard tissue uptake, and excretion

  2. Outline • Overview of fluoride metabolism • Factors affecting fluoride absorption • Soft tissue distribution of fluoride • Distribution of fluoride in calcified tissues • Renal excretion of fluoride • Fluoride in saliva

  3. H+ + F- HF ; pKa = 3.45 pH = pKa + log [A-] or pH - pKa = log [A-] [HA] [HA] At pH 2.45 log [F-] = -1 ; [F-] = 1 10 [HF] [HF] At pH 6.45 log [F-] = 3 ; [F-] = 1000 1 [HF] [HF] Fluoride ion is important for biological effects • Soluble fluoride compounds: NaF, HF, Na2PO3F • Less soluble compounds: CaF2, MgF2, AlF3 F- Diffusibility of HF explains physiological behavior of fluoride Low pH (<3.5) e.g., stomach: More as undissociated form HF pH > 3.45 e.g., blood, saliva, tissue fluid: ionized form F- dominates

  4. Fluoride metabolism FLUORIDE LUNG GI TRACT Absorbtion D i s t r i b u t i o n SOFT TISSUES HARD TISSUES PLASMA (Central compartment) ~ 50 % Steady state FECES SWEAT URINE ~ 50% in 24 hrs Excretion

  5. Absorption How fast is the absorption and distribution? Rapidly declining Bone uptake & Urinary excretion Return to normal 3-6 hours (If ingesting small amount) Peak plasma level < 30 min to an hour Ingestion

  6. In the presence of Al3+, Ca2+, Mg2+ Less absorption of fluoride Increased fecal excretion What factors affect F absorption? IV P.O. fasting Ekstrand J et al. Eur J Clin Pharm 1979; 16:211-5 P.O. milk P.O. breakfast Guess this….. Subject received 3 mg fluoride: hour Absorption ~ 100 % Absorption ~ 70 % Absorption ~ 60 % • NaF tablet, fasting stomach • NaF tablet + glass of milk • NaF tablet + calcium-rich breakfast • Intravenous injection (100% bioavailability) Treat acute F toxicity!

  7. Pentagastrin: Stimulates gastric acid secretion Bioavailability of F = 97% Cimetidine: Inhibits gastric acid secretion Bioavailability of F = 66% Pentagastrin Cimetidine AUC = cumulative plasma F level What factors affect F absorption? Higher acidity of stomach content More fluoride absorbed Why? • Fluoride is absorbed as HF • Uncharged molecule (HF) readily passes through biological membrane • HF dominates at low pH 40% of oral dose of fluoride is absorbed from the stomach

  8. Fluoride from most dental products is almost completely absorbed when swallowed!! • Acidic well absorbed x Fluoride toothpastes • NaF or SnF2 have bioavailability close to 100% • Na2PO3F has less bioavailability • Abrasive may bind fluoride (reduce absorption) APF (acidulated phosphate fluoride) gel Fluoride varnish • Remains on tooth surface 12 hrs • Plasma F concentration ~ 1-2 mg fluoride tablet

  9. 9.6 ppm F 1.2 ppm F 0.2 ppm F Fluoride in Plasma Enter Distribution Elimination Plasma = central compartment for fluoride Plasma F depend on: • F intake • Distribution • Bone & tissues • Clearance • Excretion in urine Plasma F of subjects from areas with different water F level Ekstrand J. Caries Res 1978:12:123-7

  10. Distribution Fluoride is distributed from plasma to all tissues and organs How to study tissue distribution? Administer (IV) radioisotope fluoride (18F) Determine T/P at various times until the level equilibrates (steady-state) T/P = Tissue-water-to-plasma-water ratio • Inulin (extracellular markers): T/P = 0.2-0.4 • T/P > 0.4 = agent can penetrate cells. • T/P >1 = agent can accumulate in the tissue

  11. Tissue Distribution of Fluoride T/P Brain (blood-brain barrier) Adipose tissue Heart Salivary gland Lung Liver Kidney 0.08 0.11 0.46 0.63 0.83 0.98 4.16 T/P = 0.4-0.9 Inulin (extracellular markers): T/P = 0.2-0.4 Fluoride is able to penetrate cells but not accumulate intracellularly

  12. Distribution of fluoride in calcified tissues Almost 50% of absorbed fluoride is taken up by the calcified tissues Uptake of 18F by the skeleton 4 min after IV injection in laboratory mouse Ion-exchange process: F- from plasma enters hydration shell Exchanges with OH-, CO32-, F- (apatite crystal surface) Migrates into the crystal interior (slow)

  13. Retention of fluoride in calcified tissues Young animals (& human): High portion of fluoride is deposited in the skeleton in growing dogs Puppies 80 days: F retention ~ 90% 2 years old: F retention ~ 60% Adults F retention ~ 50% Fluoride in calcified tissues is not irreversibly bound and can be released by ion-exchange or normal remodeling process

  14. Fluoride in plasma Glomerular filtration Reabsorb from renal tubules Excrete in urine 60% 30% Amount of excreted fluoride vs time after ingesting Excretion Renal clearance of fluoride Kidney is the major route of fluoride excretion Adults: 40-60% of ingested fluoride Children: Excrete a smaller % of ingested fluoride

  15. F clearance Urinary flow rate (ml/min) Acetazolamide Furosemide Early study: F Renal clearance increases with urinary flow rate. Later: Different diuretics have different effect on renal clearance of F. F excretion: Acetazolamide >>> Furosemide Why? Acetazolamide increases HCO3- pH increases

  16. Period 1-8: Mannitol diuresis Flow rate ; Urinary pH ; F clearance Period 10-12: Diamox + bicarbonate Flow rate ; Urinary pH ; F clearance Does Urinary pH or flow rate determine F clearance? Separate urinary flow rate and urinary pH Some diuretics (e.g., mannitol, saline) increase F clearance because the tubular fluid is diluted, thus pH increases. Conclusion: Tubular reabsorption of fluoride • Primarily related to urinary pH • Secondarily related to urinary flow rate

  17. Acid urine Low urinary (tubular fluid) pH: More HF more diffusion more reabsorb Less F- less remain less excrete Acid urine H++ F- HF F- H+ Alkaline urine High tubular fluid pH: Less HF less diffusion less reabsorb More F- more remain more excrete F- HF H+ H+ + F- Alkaline urine Capillary How does pH affect the renal handling of F? Tubular reabsorption of F occurs by the diffusion of HF (not F-) • HF can permeate lipid barriers • F- is charged and has large hydrated radius • incapable of permeating the tubular epithelium

  18. Why is urinary F excretion important? Acute fluoride poisoning To promote the renal excretion of fluoride by increasing urinary flow rate (diuresis) (sometimes recommended for acute fluoride poisoning) Effective only if urinary pH increases Factors that influence urinary pH: • Composition of diet • Certain drugs • Metabolic diseases Vegetarian diet more alkaline urine more fluoride excreted

  19. Other routes of fluoride excretion Feces • Fluoride in Feces: unabsorbed fluoride • < 10% ingested F • Less F absorption if diet high in Mg2+, Al3+, Ca2+ Sweat • Fluoride concentration ~ 20% of plasma. • High end sweat excretion ~ 5% ingested F • Tropical climate + prolonged exercise ~ 0.1 mg • Compare to ~ 2 mg uptake from diet • ~1 mg excreted by urine

  20. Fluoride in Saliva Saliva F-concentration Duct secretion (systemic, endogeneous) ~ 0.01-0.05 ppm, 30% less than serum F F-concentration in saliva (1) after toothbrushing (3) chewing F tablet (6) F mouthrinse (7) APF (8) 2% NaF Whole saliva: Duct secretion + exogenous F

  21. Recommended references • Ekstrand J, Fejerskov O, Silverstone LM (Eds). Fluoride in Dentistry. Copenhagen: Munksgaard 1988. Chapters 3 & 7. • Ekstrand J, Spak C-J. Vogel G. Pharmacokinetics of fluoride in man and its clinical relevance. J Dent Res 1990;69:550-55. • Whitford GM. The physiological and toxicological characteristics of fluoride. J Dent Res 1990;69:539-49. • Whitford GM. Intake and metabolism of fluoride. Adv Dent Res 1994;8:5-14. • 5. Whitford GM. The Metabolism and Toxicity of Fluoride. 2nd Ed. Monographs in Oral Science Vol 16. Chapters I – IV.

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