• Metabolic handling of ingested fluoride

• Absorption, soft-tissue distribution, hard tissue uptake, and excretion

Objectives:

DENT 5302 TOPICS IN DENTAL BIOCHEMISTRY

9 April 2007

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

Soluble fluoride compounds: NaF, HF, Na2PO3F

Less soluble compounds: CaF2, MgF2, AlF3

F-

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

Fluoride ion is important for biological effects

H+ + F- HF ; pKa = 3.45

pH = pKa + log [A-] or[HA]

pH - pKa = log [A-]

[HA]

At pH 2.45

log [F-] = -1 ;

[HF]

[F-] = 1

[HF] 10

At pH 6.45

log [F-] = 3 ;

[HF]

[F-] = 1000

[HF] 1

Diffusibility of HF explains physiological behavior of fluoride

PLASMA

(Central compartment)

SOFT

TISSUES

URINE

~ 50% in 24 hrs

HARD

TISSUES

LUNG

GI TRACT

FECES

SWEAT

FLUORIDE

~ 50 % Steady state

Fluoride metabolismFluoride metabolism

Ingestion

How fast is the absorption and distribution?

Peak plasma level < 30 min to an hour

Rapidly declining Bone uptake &

Urinary excretion

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

AbsorptionAbsorption

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 Al3+, Ca2+, Mg2+ 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?

Higher acidity of stomach content

More fluoride absorbed

What factors affect F absorption?

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

Cimetidine: Inhibits gastric acid secretion Bioavailability of F = 66%

Fluoride is absorbed as HF

Uncharged molecule (HF) readily passes through biological membrane

HF dominates at low pH

Why?

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

AUC = cumulative plasma F level

Pentagastrin

Cimetidine

NaF or SnF2 have bioavailability close to 100%

Na2PO3F has less bioavailability

Abrasive may bind fluoride (reduce absorption)

Fluoride toothpastes

xFluoride from most dental products is almost

completely absorbed when swallowed!!

APF (acidulated phosphate fluoride) gel

Acidic well absorbed

Remains on tooth surface 12 hrs

Plasma F concentration ~ 1-2 mg fluoride tablet

Fluoride varnish

Plasma = central compartment for fluoride

Fluoride in PlasmaEnter

Distribution

Elimination

0.2 ppm F

1.2 ppm F

9.6 ppm F

Plasma F of subjects from areas with 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

T/P = Tissue-water-to-plasma-water ratioT/P = Tissue-water-to-plasma-water ratio

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

DistributionDistribution

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

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 Distribution of Fluoride

Uptake of 18F by the

skeleton 4 min after

IV injection in

laboratory mouse

Distribution of fluoride in calcified tissues

F- from plasma enters hydration shell

Exchanges with OH-, CO32-, 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:

Retention of fluoride in calcified tissues

Fluoride in calcified tissues is not irreversibly bound and can

be 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 is

deposited in the skeleton

F retention ~ 50%

Puppies

Adults

in growing dogs

Kidney is the major route

of fluoride excretion

Adults: 40-60% of ingested fluoride

Children: Excrete a smaller % of

ingested fluoride

Reabsorb from renal tubules

Glomerular filtration

Fluoride in plasma

Excrete in urine

Amount of excreted fluoride vs time after ingesting

30%

60%

ExcretionExcretion Renal clearance of fluoride

Later:

Different diuretics have different

effect on renal clearance of F.

Early study:

F Renal clearance increases

with urinary flow rate.

F excretion:

Acetazolamide >>> Furosemide

Acetazolamide increases HCO3-

pH increases

Acetazolamide

Furosemide

Urinary flow rate (l/min)

F c

lear

ance

Does Urinary pH or flow 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

Capillary

HF

F-

H+

H++ F-

Acid urine Acid urine

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

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

How does pH affect the renal handling of F?

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?

Acute fluoride poisoning

Effective only if urinary pH increases

Factors that influence urinary pH:

Fluoride in Feces: unabsorbed fluoride

< 10% ingested F

Less F absorption if diet high in Mg2+, Al3+, Ca2+

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

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) chewing F tablet

(6) F mouthrinse

(7) APF

(8) 2% NaF

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 man and its clinical relevance. J Dent Res 1990;69:550-55.

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

4. 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.