Fluoride Metabolism
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Transcript of Fluoride Metabolism
• 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.