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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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slide1

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
slide2

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
slide3

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

slide4

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

slide5

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

slide6

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!

slide7

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

slide8

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
slide9

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

slide10

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
slide11

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

slide12

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)

slide13

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

slide14

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

slide15

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

slide16

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
slide17

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
slide18

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

slide19

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
slide20

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

slide21

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.