Pharmacokinetic differences between sodium fluoride and sodium monofluorophosphate and comparative bone mass increasing activity of both compounds in the rat.

After the administration of an oral dose of 80 mumol/l of NaF (CAS 7681-49-4) to rats, the area under the curve of total plasma fluoride equals 10,200 mumol.min/l. After an oral dose of 80 mumol of monofluorophosphate (MFP/CAS 10,163-15-2), two forms of fluoride appear in plasma: protein-bound MFP and diffusible fluoride. The areas under the curve of total (protein-bound + diffusible) and diffusible fluoride equal 22,200 and 8,850 mumol.min/l, respectively. The activity of MFP for increasing the bone mass of the rat was assessed with NaF as the standard. The animals were treated chronically for 100 days since weaning with food ad libitum and 5 mmol/l NaF, 5 or 2.5 mmol/l MFP solutions as the water supply. The effect obtained with 2.5 mmol/l MFP was similar to that produced by 5 mmol/l NaF, indicating a potency ratio MFP is twice as active as NaF.

Bone mass increase and glucose tolerance in rats chronically treated with sodium fluoride.

Female rats were treated with fluoride for 100 days (between 21 and 121 days of age) replacing the water supply with a 5 mM NaF solution. Bone mass was assessed by destructive physical and chemical measurements on the whole skeleton, that gave an overall view not reported previously. Bone mass (dry, fat-free weight of the skeleton/100 g of body weight) increased 7% (P less than 0.001) with respect to control animals. This phenomenon was equally evident in the head, the axial and the appendicular skeleton. Fluoride treatment did not affect the ratio ashes/organic matrix. Treated animals showed a subtle disturbance of glucose tolerance as shown by glucose tolerance tests. The disturbance was manifest as high plasma and soft tissue levels of fluoride during the period of bone mass increase. Glucose tolerance was normalized when the maximum bone mass was achieved and plasma and soft tissue fluoride returned to control levels.

Inhibitory effect of fluoride on the secretion of insulin.

The oral administration of sodium fluoride (NaF) (40 mumol/100 body weight [bw]) to fasting rats produced an immediate fall in insulin levels and the consequent increase in glycemia. These phenomena were observed with plasma fluoride concentrations 5-15 microM. Glycemia and insulin returned to normal levels within 4-5 hours, together with the washing out of fluoride from plasma and soft tissues. The insulin secretion of isolated Langerhans islets, perifused with solutions containing 5, 10, or 20 microM fluoride, was found to be significantly inhibited as a function of fluoride levels, both with basal and stimulatory concentrations of glucose. One hour after the intake of 60 mg of NaF, fasting human volunteers showed increased fluoride (5-15 microM) together with a significant fall of plasma insulin levels.

Calcium metabolism of intact and thyroparathyroidectomized rats fed a bicarbonate enriched diet.

Rats fed a bicarbonate-enriched diet become alkalotic during their feeding period (ca. 10 h/day). Alkalosis produced a significant reduction in the plasmatic concentration of ionized calcium and increased parathyroid hormone secretion confirmed by concurrent hypophosphatemia and increased urinary excretion of cAMP. Three weeks of treatment produced, however, a significant reduction of bone Ca resorption. The increased endogenous fecal excretion of calcium counteracted the enhancement of true calcium absorption. No significant change in the skeletal calcium mass was observed. Thyroparathyroidectomized rats fed the alkaline diet reduced further their rate of bone Ca resorption and increased significantly their skeletal calcium mass.

The effect of alkalosis on the glucose-mediated insulin release by the rat.

Bicarbonate loaded (alkalotic) rats had reduced plasma phosphate and ionized Ca concentrations and increased urinary cAMP excretion, phosphate clearance and pancreatic tissue uptake of extracellular calcium, all known effects of increased parathyroid hormone (PTH) secretion. Total insulin secretion after glucose challenge was enhanced in these animals. The response of alkalotic thyroparathyroidectomized rats, on the other hand, suggested exhaustion or inhibition of insulin secretion. The hypothesis is advanced that PTH, enhancing the permeability to calcium of the beta-cell membrane, compensated the effect of decreased calcium concentration in the extracellular fluid caused by alkalosis. PTH appears instrumental for homeostatic adjustments of insulin secretion.

The effect of alkalosis on the glucose-mediated insulin release by the rat.

Bicarbonate loaded (alkalotic) rats had reduced plasma phosphate and ionized Ca concentrations and increased urinary cAMP excretion, phosphate clearance and pancreatic tissue uptake of extracellular calcium, all known effects of increased parathyroid hormone (PTH) secretion. Total insulin secretion after glucose challenge was enhanced in these animals. The response of alkalotic thyroparathyroidectomized rats, on the other hand, suggested exhaustion or inhibition of insulin secretion. The hypothesis is advanced that PTH, enhancing the permeability to calcium of the beta-cell membrane, compensated the effect of decreased calcium concentration in the extracellular fluid caused by alkalosis. PTH appears instrumental for homeostatic adjustments of insulin secretion.