04 07 08 Fluoride Metabolism

8/13/2019 04 07 08 Fluoride Metabolism

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• Metabolic handling of ingested fluoride• Absorption, soft-tissue distribution, hard tissue uptake, and excretion

Objectives:

DENT 5302 TOPICS IN DENTAL BIOCHEMISTRY7 April 2008

Outline

Overview of fluoride metabolism

Factors affecting fluoride absorption

Distribution of fluoride in calcified tissues

Soft tissue distribution of fluoride

Renal excretion of fluoride

Fluoride in saliva

Overview of fluoride metabolism

F supplement (drops, tablets)

Water fluoridation

‘Topical’ fluoride products

Systemic intake of fluoride

Fluorosis Acute toxicity

Fluoride is hazardous

Fluoride is added to water supplies and incorporated indental products that are commercially available.Although most of these products are for topical

application, a portion of them are swallow and beingabsorbed. Fluoride is a hazardous substance. Systemicintake of large doses can have side effect from mild tosevere, or even death. To understand the biologicaleffect of fluoride after systemic intake, we needthorough knowledge of the fluoride metabolism.

Soluble fluoride compounds: NaF, HF, Na 2PO 3F

Less soluble compounds: CaF 2, MgF 2, AlF 3

F -

Low pH (<3.5) e.g., stomach:More as undissociated form HF

Fluoride ion is impor tant for biolog ical effects

H+ + F - HF ; pKa = 3.45

pH = pK a + log [A -] or [HA]

pH - pK a = log [A -]

[HA]

At pH 2.45log [F -] = -1 ;

[HF]

[F-] = 1[HF] 10

At pH 6.45log [F -] = 3 ;

[HF]

[F-] = 1000[HF] 1

Diffusibility of HF explains physiological behavior of fluoride

pH > 3.45 e.g., blood, saliva,tissue fluid: ionized form F - dominates

Fluoride can be in the soluble compounds or less soluble compounds. Fluoride ions are releaseddepending on the solubility of the compound. Fluoride ion is important for the biological effects.

Fluoride ions can reversibly combine with hydrogen ions to form hydrogen fluoride or hydrofluoric acid.Hydrofluoric acid has pKa 3.45. Any fluoride present at a low pH such as in the stomach will exist mainlyin the undissociated form as HF. At pH above 3.45, like in blood plasma, saliva, and tissue fluid, fluoridewill be in the ionized form. Much of the physiological behavior of fluoride can be explained in terms ofthe diffusibility of HF.

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Fluoride metabolism

PLASMA

(Central compartment)

SOFTTISSUES

URINE~ 50% in 24 hrs

HARDTISSUES

LUNGGI TRACT

FECESSWEAT

FLUORIDE

~ 50 % Steady state

The overall metabolism of fluoride can be divided into3 steps: absorption, distribution, and excretion. Mainlyfluoride is absorbed and enters the body through thelungs or the gastrointestinal tract. Plasma is the centralcompartment where the ions pass before beingdistributed and eliminated. Roughly 50% of theabsorbed fluoride is excreted in the urine during thefollowing 24 hours. Most of the remaining 50% will

become associated with calcified tissue.

Note that fluoride in calcified tissues is not irreversibly bound. For example, it may be released duringnormal remodeling of bone. In soft tissues, fluoride has a steady state distribution between theintracellular and extracellular fluids. When the plasma level of fluoride is rising or falling, there is a

parallel change in the intracellular fluids.

Abs orpti on

Ingestion

How fast is the absorption and distributio n?

Peak plasma level< 30 min to an hour

Rapidly decliningBone uptake &

Urinary excretion

Return to normal 3-6 hours(If ingesting small amount)

Factors affecting fluoride absorption

After ingestion, within minutes we can detectincreased plasma fluoride levels, which mean thatfluoride is readily absorbed from the stomach. The

peak level usually occurs during the first hour, can beless than 30 min. Then the plasma level will rapidlydecline due to bone uptake and urinary excretion. Ifthe amount of fluoride ingested is small (not morethan a few mg), the plasma level will return to

normal within 3-6 hours.

This graph shows plasma fluorideconcentration in a subject after received 3 mgfluoride in 4 different ways: NaF tablet takenon a fasting stomach, NaF tablet taken with aglass of milk, NaF tablet taken with calcium-rich breakfast, and the same dose of fluoride byintravenous injection, which has 100%

bioavailability.1. NaF tablet, fasting stomach

2. NaF tablet + glass of milk

3. NaF tablet + calcium-rich breakfast

4. Intravenous injection (100% bioavailability)

Guess this…..

Absorption ~ 100 %

Absorption ~ 70 %

Absorption ~ 60 %

In the presence of Al 3+ , Ca 2+, Mg 2+ Less absorption of fluoride

Increased fecal excretion

Ekstrand J et al.Eur J Clin Pharm 1979; 16:211-5

P.O. fasting

P.O. milk

P.O. breakfast

IV

Subject received 3 mg fluoride: hour

What factors affect F absorption?

The absorption of F taken on a fasting stomachwas about 100%. Taken with milk decreasedabsorption to about 70%, and 60% withcalcium-rich breakfast.

The decreased absorption is caused by the binding of fluoride with certain ions, esp Al, Mg, Ca. In thiscase, the fecal excretion of fluoride increases. The ability of calcium to reduce the absorption of F is the

basis for treating acute F toxicity by giving calcium-containing solution.

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Higher acidity of stomach content

More fluoride absorbed

What factors affect F absorpti on?

Pentagastrin: Stimulates gastric acid secretion Bioavailability of F = 97%

Cimetidine: Inhibits gastr ic acid secretion Bioavailability of F = 66%

Fluoride is absorbed as HF

Uncharged molecule (HF)readily passes throughbiological membrane

HF dominates at low pH

Why?

40% of oral dose of fluoride is absorbed from the stomach

AUC = cumulative

plasma F level

PentagastrinCimetidine

This experiment, rats were given Cimetidine toinhibit gastric acid secretion or Pentagastrin tostimulate gastric acid secretion.The bioavailability of fluoride in thePentagastrin group was 65-97%, comparing to

66% in the Cimetidine group. This studyindicates that the permeation of fluoride throughthe gastric mucosa is pH dependent.The higher acidity of stomach content increasesthe absorption of fluoride. The reason is

because HF is the dominate form at low pH.

Fluoride is absorbed as HF, which is an uncharged molecule and can readily pass through biologicalmembranes. Research has shown that 40% of oral dose of fluoride is absorbed from the stomach.

Fluoride from most topical dental products isalmost completely absorbed when swallowed!!

NaF or SnF 2 have bioavailability close to 100%

Na 2PO 3F has less bioavailability

Abrasive may bind fluoride (reduce absorption)

Fluoride toothpastes xFluoride from most dental products is almost

completely absorbed when swallowed!!

APF (aci dul ated phos phate fluor ide) gel

Acidic well absorbed

Remains on tooth surface 12 hrs

Plasma F concentration ~ 1-2 mg fluoride tablet

Fluoride varnish

The bioavailability of NaF or SnF 2 in fluoridetoothpastes is close to 100%, and somewhat lessfor monofluorophosphate. Abrasive intoothpaste may bind to fluoride and reduce theabsorption.

F from APF (acidulated phosphate fluoride) gelis well absorbed. Other topical F products with

high fluoride content include fluoride varnish.The varnish remains on the tooth surface forupto 12 hours. The increase in plasma fluorideconcentration is equivalent to ingesting a 1-2mg fluoride tablet.

Distribution of fluoride in soft tissues and

calcified tissuesPlasma = central compartment for fluoride

Fluoride in PlasmaEnter

Distribution

Elimination

0.2 ppm F1.2 ppm F

9.6 ppm F

Plasma F of subjects from areaswith different water F level

Plasma F depend on:

F intake

Distribution

Bone & tissues

Clearance

Excretion in urine

Ekstrand J. Caries Res 1978:12:123-7

Fluoride in plasma: Plasma is the centralcompartment for fluoride, where fluoride must

pass for its distribution elsewhere in the bodyand for its elimination. The concentration offluoride in plasma depends on fluoride intake(chronic or recent), distribution to bone andother tissues, and clearance or excretion inurine. This graph shows an example fromsubjects living in areas with different water Flevel.

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Distribution

T/P = Tissue-water-to-plasma-water r atioT/P = Tissue-water-to-plasma-water r atio

Administer (IV) radioisotope fluoride ( 18F)

Determine T/P at various times until the level equilibrates (steady-state)

Fluoride is distributed from plasma to all tissues and organs

How to study tissue distribution?

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

Distribution to soft tissues: Fluoride isdistributed from plasma to all tissues andorgans.

How to study tissue distribution? The indexfor tissue distribution is Tissue-water-to-

plasma-water ratio (T/P). Radioisotopefluoride ( 18F) is administered intravenously,and T/P ratio is determined when the levelequilibrates (steady-state). Inulin is used as anextracellular marker. T/P of Inulin = 0.2-0.4.

Therefore, an agent with T/P higher than 0.4means that it can penetrate cells. If T/P >1,that agent can accumulate in the tissue.

In most organs, such as in liver, lung, heart,

salivary gland, T/P ratio of fluoride is 0.4-0.9.This range means that fluoride is able to

penetrate cells (T/P higher than Inulin which isan extracellular marker) but fluoride is notaccumulated intracellularly (T/P is less than 1).Some exceptions where fluoride cannot

penetrate into are brain (blood-brain barrier)(0.08) and adipose tissues (0.11). T/P ratio offluoride in kidney is 4.16. This value does notindicate accumulation but is related toexcretion of fluoride by kidney.

T/P

Brain (blood-brain barrier) Adipose t is sueHeartSalivary glandLungLiver Kidney 4.16

0.080.110.460.630.830.98

Inulin (extracellular markers): T/P = 0.2-0.4

T/P = 0.4-0.9

Fluoride is able to penetrate cells

but not accumulate intracellularly

Tissue Distribut ion of Fluoride

Distribution to calcified tissues: Almost 50%of absorbed fluoride is taken up by thecalcified tissues. Fluoride is an avid calcifiedtissue seeker. Only 4 min after intravenousinjection of fluoride to this mouse, the skeleton

is clearly labeled.

Uptake of 18F by theskeleton 4 min after

IV injection inlaboratory mouse

Distribution of fluoride in calcified tissues

F - from plasma enters hydration shell

Exchanges with OH -, CO 32-, F -

(apatite crystal surface)

Migrates into the crystal interior (slow)

Almost 50% of absorbed fluoride is taken up by the calcified tissues

Ion-exchange process:

Fluoride ions from tissue fluid first enter thehydration shell surrounding the apatitecrystallites. Then it exchanges with negativeions (hydroxyl, carbonate, or even anotherfluoride) in the lattice at the crystal surface.Some of the fluoride at the surface mightmigrate into the crystal interior, which happensvery slowly unless fluoride is acquired duringthe crystal growth.

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Retention of fluoride in calcified tissues

Fluoride in calcified tissues is not irreversibly bound and canbe released by ion-exchange or normal remodeling process

80 days: F retention ~ 90%2 years old: F retention ~ 60%

Young animals (& human):High portion of fluoride isdeposited in the skeleton

F retention ~ 50%

Puppies

Adul ts

in growing dogs

In young animals (and humans) a relativelyhigh portion of fluoride is deposited in theskeleton.

In this study, fluoride retention in young puppies is about 90%, and reduced to 60% at 2years old. In adults, fluoride retention is onaverage 50%. It should be emphasized thatfluoride in calcified tissues is not irreversibly

bound and can be released by ion-exchange or

normal remodeling processes.

Excretion of fluoride

The major route of fluoride excretion is by the

kidneys (= Renal clearance). After fluoridefrom plasma enters renal tubules by filtration atthe glomeruli, some will be reabsorbed and theremainder will be excreted in urine.

Excretion

Kidney is the major routeof fluoride excretion

Adults: 40-60% of ingested fluoride

Children: Excrete a smaller % ofingested fluoride

Reabsorb fromrenal tubules

Glomerular filtration

Fluoride in plasma

Excrete in urine

Amount of excreted fluoridevs time after ingesting

30%

60%

Renal clearance of fluoride

In adults, renal clearance is about 40-60% ofingested fluoride. In children, a smaller

percentage of ingested fluoride is excreted.This graph shows that nearly 30% of fluorideingested was excreted in about 6 hours, and60% in 24 hours.

Early studies show a positive correlation between renal clearance of fluoride and urineflow rate. Renal clearance of fluorideincreases when urinary flow rate increases. Alater study found that different diuretics havedifferent effects on renal clearance of F. Asshown here, the increase in F excretion inAcetazolamide group is 9 times higher than in

Furosemide. There must be something elsethan the urinary flow rate alone that governsrenal clearance of F. Acetazolamide promotesthe excretion of sodium bicarbonate whichincreases urinary pH.

Later:Different diuretics have differenteffect on renal clearance of F.

Early study:F Renal clearance increaseswith urinary flow rate.

F excretion: Acetazolamide >>> Furosemide

Acetazolamide increases HCO 3-

pH increases

Acetazol amide

Furosemide

Urinary flow rate ( l/min)

F c

l e a r a n

c e

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Does Urinary pH or fl ow rate determine F clearance?

Period 1-8: Mannitol diuresis

Flow rate ; Urinary pH ; F clearance

Period 10-12: Diamox + bicarbonate

Flow rate ; Urinary pH ; F clearance

Primarily related to urinary pH

Secondarily related to urinary flow rate

Some diuretics (e.g., mannitol, saline)increase F clearance because the

tubular fluid is diluted, thus pH increases.

Separate urinary flow rate and urinary pH

Conclusion: Tubular reabsorption of fluoride

Is urinary pH or flow rate the determinant offluoride excretion? A study was conducted to

proof this point by separating urinary flow rate pH. From period 1-8, diuresis was induced bymannitol. As expected, fluoride clearanceincreased with urinary flow rate. At the sametime urinary pH also increased. In period 10-12, the mannitol was replaced with sodium

bicarbonate and Diamox. Diamox reducedflow rate while bicarbonate increased pH.The fractional excretion of fluoride increased.

Therefore, the fluoride clearance is affected by urinary pH, not urinary flow rate. Some diuretics(mannitol or saline) increase fluoride excretion because the diuretic dilutes the tubular fluid, thus increases

pH. In conclusion, tubular reabsorption of fluoride is primarily related to urinary pH and onlysecondarily related to urinary flow rate.

Capillary

HF

F -

H+

H++ F -

Aci d ur ine Aci d ur ine

Low urinary (tubular fluid) pH:

More HF more diffusion more reabsorb

Less F - less remain less excrete

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

Alk alin e uri ne

High tubular fluid pH:

Less HF less d iffus io n less reabso rb

More F - more remain more excrete

F -

HF

H+

H+ + F -

Alk alin e uri ne

How does pH affect the renal handling of F? How does pH affect the renal handling of F?

When F is reabsorbed from renal tubules, theamount of F reabsorption can vary from 20-95%depending on pH of the tubular fluid. Thischaracter can also be explained by the diffusionof undissociated HF across the tubularepithelium.

HF can permeate lipid barriers, whereas thefluoride ion is charged and has a large hydratedradius, therefore cannot permeate the tubularepithelium.

When tubular fluid (and hence urine) becomes more acidic, the fraction of fluoride in HF form isincreased, and diffuses from the tubular lumen to the interstitial fluid. Usually the pH of the interstitialfluid is relatively high, about 7, so HF dissociates and releases fluoride ions. Fluoride ions can thendiffuse into capillaries and return to plasma. As a result, less fluoride is excreted when tubular fluid andurine is acidic.

Question:

Which diuretic is the most effective for treating acutefluoride toxicity?

a. Acetazolamide (increases flow rate and HCO3-)

b. Mannitol (increase urinary flow rate)

c. saline (increase urinary flow rate)

When tubular fluid becomes more alkaline, thefraction of fluoride in HF form is less, and not manyHF diffuse into the interstitial fluid. Thus lessfluoride diffuses into capillaries and return to plasma.The large amount of ionic fluoride which cannotdiffuse through the tubular membrane is left in therenal tubule to be excreted. As a result, more fluorideis excreted when tubular fluid and urine is alkali.

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Composition of diet

Certain drugs

Metabolic diseases

Vegetarian diet more alkaline urine more fluoride excreted

To promote the renal excretion of fluoride by increasing urinary flow rate (diuresis)

(sometimes recommended for acute fluoride poisoning)

Why is urinary F excretion important?

Acu te fl uor ide p ois oni ng

Effective only if urinary pH increases

Factors that influence urinary pH:

Why is urinary fluoride excretion important?

In case of acute fluoride poisoning, to promote therenal excretion of fluoride by increasing urinary flowrate will be effective only if the method also increasesurinary pH.

Factors that influence urinary pH affect the excretion offluoride. For example, the composition of diet, certaindrugs, and some metabolic diseases. Interestingly, avegetarian diet promotes more alkaline urine and hencemore fluoride excretion.

Fluoride in Feces: unabsorbed fluoride

< 10% ingested F

Less F absorption if diet high in Mg 2+, Al3+, Ca 2+

Other routes of fluoride excretion

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

Feces

Sweat

Other routes of fluoride excretion, which are lessimportant, are via sweat and feces. Most of the

fluoride in feces is never absorbed, usually it is lessthan 10% of the ingested amount. If diet contains highconcentration of cations (Mg 2+ 3+, Al , Ca 2+), lessfluoride is absorbed and more is excreted in feces.

Fluoride concentration in sweat is ~ 20% of plasma. Intropical climates during prolonged exercise, theexcretion of fluoride in sweat is about a tenth of amilligram. This values is quite small compared to 2mg uptake from diet and a milligram of fluorideexcreted by urine.

Fluoride in Saliva

Duct secretion (systemic, endogeneous)

~ 0.01-0.05 ppm, 30% less than serum F

Saliva F-concentration

Whole saliva:

Duct secretion

+ exogenous F

F-concentration in saliva(1) after toothbrushing(3) ch ewing F tablet(6) F mouthri nse(7) APF(8) 2% NaF

Fluoride in saliva

Concentration of fluoride in saliva from systemicsources (endogeneous), collected from salivary ducts,is around 0.01-0.05 ppm, about 30% less than thecorresponding serum F concentrations. Whole saliva Fconcentrations are higher than the duct secretion

because of exogenous fluoride. Graphs show F-concentration in saliva after toothbrushing (1), chewingF tablet (3), mouthrinse (6), topical application of APF(7) and 2% NaF (8).

Recommended references

1. Ekstrand J, Fejerskov O, Silverstone LM (Eds). Fluoride in Dentistry.Copenhagen: Munksgaard 1988. Chapters 3 & 7.

2. Ekstrand J, Spak C-J. Vogel G. Pharmacokinetics of fluoride in manand its clinical relevance. J Dent Res 1990;69:550-55.

3. Whitford GM. The physiological and toxicological characteristics offluoride. J Dent Res 1990;69:539-49.

4. Whitford GM. Intake and metabolism of fluoride. Adv Dent Res1994;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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04 07 08 Fluoride Metabolism

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