FLUORIDE METABOLISM HENDRA WIJAYA

Fluoride Main sources include drinking water and plants (spinach, lettuce, onions) 99% is found in bones and teeth Average daily intake: 1.5 – 4.0 mg/day Function to promote mineralization of calcium and phosphate. Inhibits bacterial growth in mouthdecreases cavity formation. Fluoride supplementation is available in both oral and topical forms: Oral: mainly sodium fluoride (Pediaflor Drops) Topical: either sodium or stannous fluoride (Fluorigard, Karigel, Fluoral)

Fluoride ion is important for biological effects Soluble fluoride compounds: NaF, HF, Na2PO3F Less soluble compounds: CaF2, MgF2, AlF3 F- H+ + F- HF ; pKa = 3.45 pH = pKa + log [A-] or [HA] pH - pKa = log [A-] Diffusibility of HF explains physiological behavior of fluoride At pH 2.45 log [F-] = -1 ; [HF] [F-] = 1 10 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 At pH 6.45 log [F-] = 3 ; [HF] [F-] = 1000 1

Fluoride metabolism Absorbtion D i s t r i b u t i o n Excretion 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

ABSORPTION 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

What factors affect F absorption? Subject received 3 mg fluoride: hour NaF tablet, fasting stomach NaF tablet + glass of milk NaF tablet + calcium-rich breakfast Intravenous injection (100% bioavailability) Absorption ~ 100 % Absorption ~ 70 % Absorption ~ 60 % In the presence of Al3+, Ca2+, Mg2+ Less absorption of fluoride Increased fecal excretion

What factors affect F absorption? Pentagastrin: Stimulates gastric acid secretion Bioavailability of F = 97% Cimetidine: Inhibits gastric acid secretion Bioavailability of F = 66% 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

Absorption Fluoride from most dental products is almost completely absorbed when swallowed!! 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 Acidic well absorbed Fluoride varnish Remains on tooth surface 12 hrs Plasma F concentration ~ 1-2 mg fluoride tablet

FLUORIDE IN PLASM Plasma = central compartment for fluoride 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

FLUORIDE 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

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

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)

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

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

Acetazolamide increases HCO3- 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 Acetazolamide Furosemide Why? Acetazolamide increases HCO3- pH increases

Does Urinary pH or flow rate determine F clearance? Separate urinary flow rate and urinary pH Period 1-8: Mannitol diuresis Flow rate ; Urinary pH ; F clearance Period 10-12: Diamox + bicarbonate Flow rate ; Urinary pH ; F clearance 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

H++ F- HF F- 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 Capillary HF F- H+ H++ F- Acid urine Low urinary (tubular fluid) pH: More HF more diffusion more reabsorb Less F- less remain less excrete Alkaline urine High tubular fluid pH: Less HF less diffusion less reabsorb More F- more remain more excrete F- HF H+ H+ + F-

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

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

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

Fluoride Deficiency & Toxicity Associated with an increase in dental caries Toxicity GI upset, excessive production of saliva, watery eyes, heart problems, coma Dental fluorosis Skeletal fluorosis UL .1 mg/kg body weight daily up to 8 years old Most risk is 8 yo or younger Mottling or fluorosis with chronic intake