Metabolism of the complex monofluorophosphate-alpha 2-macroglobulin in the rat.

Sodium monofluorophosphate (MFP) is a drug used in the treatment of primary osteoporosis. Following the intake of MFP, a small fraction of the drug is absorbed intact and forms a complex with alpha 2-macroglobulin (MFP-alpha 2M) inactivating the antiproteasic activity of the globulin. The complex has been shown to occur in the serum of rats and human being. This paper reports data on the metabolism of this complex in the rat. In vitro experiments showed that liver and bone tissue remove MFP-alpha 2M from the incubation medium. When the experiments were pursued beyond the time needed to reduce the complex concentration to very low levels, fluorine (F) reappears in the medium in two forms: bound to low molecular weight macromolecule/s (2,200 +/- 600 Da) and as ionic F. Concentrations of these F fractions increase while that of the complex decreases as a function of time. In vitro, uptake of the complex by liver or bone tissue was not affected by the presence of colchicine or methylamine. These drugs, however, inhibited intracellular metabolism of the complex, as indicated by the impairment of the return of F species to the extracellular space and the increase in F content of the tissue. The cellular receptors responsible for the uptake of the complex in liver and bone are insensitive to low concentration of calcium and inhibited by polyinosinic acid[5]. These features characterize the [quot ]scavenger[quot ] receptor, one of the two receptor types known to remove inactive alpha 2M from the circulation. Injection of polyinosinic acid [5] to living rats also hindered the disappearance of the complex from serum. It is concluded that the metabolism of the MFP-alpha 2M complex involves binding to receptors, uptake by cells, lysosomal degradation and return of F bound to low molecular weight macromolecule/s to the extracellular space. It is assumed, however, that inorganic F is the final product of lysosomal hydrolysis of the protein moiety.

A clinical test for calcium absorption in climacteric women: a two tracer, single blood sample procedure with corrections for body size and skeletal turnover

Se ha desarrollado un método que estima la relación: absorción neta de calcio/calcio ingerido, mediante el empleo de dos trazadores (45Ca y fluoruro de sodio). Estos trazadores estiman, respectivamente, la absorción de calcio y el turnover óseo. Cada sujeto recibió una dosis oral de 700 micronmoles de fluoruro de sodio en ayunas, recogió la orina emitida en las 24 horas siguientes con el objeto de medir la fracción excretada de fluoruro y determinar la retención corporal de fluoruro (WBRF) que estima el turvnover óseo: WBRF = 100 (1 - (Fluoruro urinario/dosis de fluoruro)). Veinticuatro horas después de la dosis de fluoruro, cada paciente recibió 2 microcuries de 45Ca en 15 ml de leche. Se les extrajo sangre 5 horas más tarde para medir la radioactividad en el plasma y calcular la fraccioón del isótopo en el líquido extracelular, estimado en 15% del peso corporal: balances entre 0 y -100 mg Ca/d (n = 30) exhibieron una relación sigmoides en función de la WBRF (AU)

A clinical test for calcium absorption in climacteric women. A two tracer, single blood sample procedure with corrections for body size and skeletal turnover.

This paper reports a two tracers (45Ca for estimating calcium absorption and stable fluoride for assessing skeletal turnover), single blood sample procedure that estimates the absorption of calcium in climacteric women. The proposed technique determines the percentage (Ac) of the dose of 45Ca administered orally (in the fasting state, diluted with 150 ml of milk), present in the extracellular fluid (estimated as 15

of body wt) five hours after intake, corrected for skeletal turnover (assessed by the whole body retention of fluoride). In a series of 13 patients, Ac has been found to be operationally equivalent to the ratio: net Ca absorption/Ca intake, measured under balance conditions. The calcium balances of 60 climacteric women, estimated as: net Ca absorption (Ca intake factored by Ac) minus calciuria was found, as expected, to be correlated with skeletal turnover.

In postmenopausal osteoporosis the bone increasing effect of monofluorophosphate is not dependent on serum fluoride.

According to previous pharmacokinetic studies the bioavailability of fluorine (F) from sodium monofluorophosphate (MFP) doubles that of sodium fluoride (NaF). This paper reports a study designed to verify whether the vertebral bone mass increasing effect of NaF (30 mg F/day) was comparable to that of MFP (15 mg F/day), given for 18 months to osteoporotic postmenopausal women. The BMD of lumbar vertebrae of both groups showed significant increases (MFP: 60 +/- 15 mg/cm2, NaF: and 71 +/- 12 mg/cm2) over basal levels (P < 0.001). The difference between treatments was not significant (P = 0.532). The serum levels of ionic F (the mitogenic species on osteoblasts) were not related to the above mentioned effects. In NaF-treated patients, the fasting levels of total serum F increased significantly (6.7 +/- 0.9 microM vs. Basal: 2.0 +/- 0.8 microM; P < 0.001). This phenomenon was accounted for by ionic fluoride that increased over 20-fold (6.5 +/- 1.9 microM vs. Basal: 0.3 +/- 0.04 microM). In MFP-treated patients the fasting serum levels of total (7.0 +/- 0.7 microM vs. Basal: 2.2 +/- 0.9 M) and diffusible F (0.5 +/- 0.02 microM vs. Basal 0.2 +/- 0.02 microM) increased significantly (P < 0.001). The increase in the non diffusible F fraction is accounted for by protein-bound F, probably by the complexes formed between MFP and alpha 2-macroglobulin and C3. Serum diffusible F was formed by two fractions: ionic F and F bound to low molecular weight macromolecule/s (2,200 +/- 600 Da), in approximately equal amounts. The general information afforded by the present observations support the hypothesis that ionic F is released progressively during the metabolism of MFP bound to alpha 2-macroglobulin and C3. These phenomena explain why comparable effects to those obtained with 30 mg F/d of NaF could by obtained with one half the dose of MFP.