Magnesium hydroxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1969

Materials and methods

Objective of study:

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Renal handling of magnesium
- Short description of test conditions: 30 dogs received 1.0 - 3.0 µg Mg/min/kg bw with gradual elevation of diffusible serum magnesium (dSMg) to 12 mg/100 mL.
- Parameters analysed / observed: Clearance of magnesium

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Magnesium chloride

EC Number:

232-094-6

EC Name:

Magnesium chloride

Cas Number:

7786-30-3

Molecular formula:

Cl2Mg

IUPAC Name:

magnesium dichloride

Radiolabelling:

no

Test animals

Species:

dog

Strain:

other: Mongrel

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 12 - 27 kg

Administration / exposure

Route of administration:

infusion

Vehicle:

other: 2.5% dextrose in water

Duration and frequency of treatment / exposure:

3-6 hours

Doses / concentrations

Remarks:

Doses / Concentrations:
1.0 - 3.0 µg Magnesium/min per kg body weight

No. of animals per sex per dose / concentration:

No of animals per study:
1) 8; 2) 3; 3) 3; 4) 2; 5) 5; 6) 5; 6) 5; 7) 4

Control animals:

no

Details on study design:

The following studies were performed:

EXPT 1). Magnesium chloride or sulfate infusion alone (8 dogs, 10 experiments):
4 of the 8 animals were trained and studied in the unanaesthetised state. Water diuresis was maintained by the infusion of 2.5% dextrose in water delivered at a rate equal to urine flow. In 8 experiments, MgCl2 was infused following 3 control clearance periods; in 3 of these studies additional clearance periods were collected for 90 mins after the MgCl2 infusion was discontinued to evaluate renal handling of magnesium with a falling as well as rising serum level. In an additional 2 experiments, an equivalent amount of magnesium was given in the form of MgSO4 to investigate the influence of this non-reabsorbable anion.

EXPT 2). Simultaneous infusion of 0.9% NaCl and MgCl2 (3 anaesthetised dogs):
Normal saline was infused for 60 min at 20 mL/min and subsequently at a rate adjusted to urine flow. Three control clearance periods were obtained after the first 60 min of saline infusion and MgCl2 infusion was then superimposed throughout the remainder of the study.

EXPT 3). Simultaneous infusion of 0.9% NaCl, CaCl2 and MgCl2 (3 anaesthetised dogs):
Normal saline was administered as in experiment 2 above. After 3 control clearance periods, both CaCl2 (10-20 mg Ca/kg/h) and MgCl2 were infused throughout the experiment.

EXPT 4). Simultaneous infusion of 0.9% NaCl and MgCl2 in dogs pretreated with deoxycorticosterone acetate (DCA) (2 anaesthetised dogs): Each dog received intramuscular injections of 20 mg DCA daily for 7 days prior to the experiment and an additional 10 mg DCA on the morning of the study. The protocol followed was identical to that described in EXPT 2.

In each experiment of the studies 2, 3 and 4 above, a triple lumen catheter with a balloon attached to its distal end was inserted via the right femoral artery into the aorta to a level above the renal arteries. Abrupt inflation of the balloon led to cessation of urine flow. Intra-aortic pressure was monitored both proximal and distal to the balloon by mercury manometers. While serum magnesium was stable at a high level towards the end of each experiment, glomerular filtration rate was acutely reduced by inflation of the intra-aortic balloon. Five minutes were allowed for the intra-aortic pressure to stabilise and 3 to 6 clearance periods of 57 min duration were then collected.

EXPT 5). Infusion of MgCl2 in dogs pretreated with DCA (5 anaesthetised dogs): Each dog received DCA as described in EXPT 4. On the day of the study, 3 control periods were collected and then MgCl2 was infused at 1.0-3.0 µg Mg/min/ kg bw for 6 h.

EXPT 6). Simultaneous infusion of CaCl2 and MgCl2 (5 anaesthetised dogs): CaCl2, added to 2.5% dextrose in water was infused to deliver 7 mg Ca/kg per hour throughout the entire experiment. After 60 min, 3 control periods were obtained and MgCl2 was then infused for 6 additional hours.

EXPT 7). Parathyroid extract administration during MgCl2 infusion (4 anaesthetised dogs): After 3 control clearance periods, MgCl2 was infused for 6 h. 200 units of parathyroid extract (PTE) were injected with the institution of MGCl2 infusion and another 100 units of PTE was given every 2 h thereafter. A total of 400 units were given.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The analysis of data from eight experiments with magnesium chloride infusion alone demonstrated a reabsorptive Tm for magnesium of approximately 140 ug/min per kg body weight. This Tm was reached when filtered magnesium was 280 µg/min per kg body weight. There was a substantial decrease in Tm magnesium during saline or calcium infusion and following chronic treatment with DCA; the Tm values were 80, 85, and 75 µg/min per kg body weight respectively. Under these conditions the Tm values were reached at filtered loads of 150 µg/min per kg body weight.

Details on excretion:

In the majority of experiments glomerular filtration rate (GFR) remained relatively stable during the infusion of magnesium salts, although a fall in GFR of 10-30% occurred in 8 of 32 experiments when the blood levels of magnesium were highest. In both the anesthetized and unanesthetized dogs, magnesium infusion caused a rapid increase in magnesium excretion. The percent of filtered magnesium excreted ((magnesium clearance (Cmg)/creatinine clearance (Ccr)) X 100) rose steeply as diffusible serum magnesium was elevated from 1.5 to 7.0 mg/100mL with a further increase in the levels of diffusible serum magnesium (7.0-12.0 mg/100mL), the fraction of filtered magnesium excreted increased much more slowly, reaching 60-75%. The relationship between (Cmg/Ccr) X 100 and the diffusible magnesium content of the serum was similar whether serum magnesium was rising or falling. The percent of filtered magnesium excreted during MgSO4 infusion was not different from that observed with MgCl2 infusion for any given level of diffusible serum magnesium.

With the rise in urinary magnesium, calcium excretion increased immediately. Urinary calcium constituted 15-20% of the filtered load when the diffusible levels of serum magnesium reached 7.0-12.0 mg/100mL. Sodium excretion also increased with magnesium infusion, but the increment was less pronounced than that of calcium and did not occur until 2 hours after the initiation of the magnesium infusion.

The simultaneous infusion of MgCl2 and normal saline to normal and DCA-treated dogs and the infusion of MgCl2, normal saline, and CaCl2 to normal dogs resulted in the excretion of a greater percent of filtered mangesium for any given level of serum magnesium as compared to the data from MgCl2 infusion alone.

Parathyroid extract administration during magnesium infusion caused a decrease in the percent of filtered magnesium excreted in all experiments as compared with results observed during MgCl2 infusion alone. This effect became apparent 4 to 5 hours after the first injection of PTE. With PTE administration, urinary calcium was also lower when compared to results from experiments with MgCl2 infusion alone.

Any other information on results incl. tables

The data strongly suggest that the decrease in tubular reabsorption of magnesium observed at physiological serum magnesium levels and filtered loads during saline infusion, calcium infusion, or following chronic DCA treatment is probably the result of reduced Tm magnesium. The observations that acute reduction in glomerular filtration rate had little or no effect on Tm magnesium indicate that the latter is independent of glomerular filtration rate. The tubular mechanism for reabsorption of magnesium may be saturated by a sufficient rise in plasma concentration and filtered load. Reduction in glomerular filtration rate would be expected to have no influence on maximum reabsorptive capacity if filtered load exceeds the saturation limit. A similar lack of dependence of maximal tubular reabsorption on glomerular filtration rate has been reported for other substances such as phosphate and glucose for which a maximum reabsorptive capacity exists.

 

The lack of difference in the relationship between (Cmg/Ccr) X 100 and the concentration of diffusible magnesium in serum while the latter was either rising during MgCl2 infusion of falling after the infusion had been discontinued indicates that the change in filtered magnesium is the primary determinant of urinary excretion at these serum levels. Furthermore, these observations suggest that hormonal factors, which might be brought into play by hypermagnesemia, have little if any effect on renal handling of magnesium under these experimental conditions.

 

In the present study, magnesium excretion did not exceed filtered load during the infusion of large amounts of magnesium chloride or sulphate. Even when factors known to decrease tubular magnesium reabsorption such as NaCl infusion, CaCl2 infusion and chronic DCA treatment were superimposed on magnesium chloride infusion, the percent of filtered magnesium excreted did not exceed unity.

 

The data show that in every case the Cmg/Ccr fell with the reduction in GFR and filtered magnesium. It appeared, therefore, that magnesium, like sodium and calcium, is handled by the kidney by filtration and tubular reabsorption alone. However, a secretory process of small magnitude, if at all present, might not be identified with the clearance technique. Such a theoretical secretory system, if quantitatively limited and quickly saturated, at or near the normal serum magnesium level, would be obscured as serum magnesium increases. The subsequent behavior of the renal handling of magnesium would appear to be entirely the result of filtration and reabsorption alone.

 

The intramuscular injection of parathyroid extract decreased fractional magnesium excretion in every animal despite the presence of high filtered magnesium which favors increased excretion. Fractional calcium excretion was also reduced raising the possibility that the change in urinary magnesium was secondary to that of calcium. This supposition seems remote. Since the augmentation of urinary calcium occurred secondary to magnesium loading and since the relative rates of magnesium reabsorption and excretion was so great, it is unlikely that changes in urinary calcium can influence magnesium excretion under these experimental conditions. It is more reasonable that both magnesium and calcium excretion were affected simultaneously by thyroid extract. The present data, therefore, support the concept that parathyroid hormone can enhance tubular magnesium reabsorption per se.

Applicant's summary and conclusion

Conclusions:

The authors studied the renal excretion of magnesium sulphate in dogs under various conditions. They concluded that magnesium like sodium and calcium is filtrated and reabsorbed in the kidneys of dogs. They did not find any evidence of tubular secretion. A maximum tubular reabsorption capacity of 140 μg/min/kg bw was reported.

Executive summary:

In a study from Massry et al., renal handling of Mg was evaluated in 30 dogs receiving 1.0 -3.0 µg Mg/min per kg body weight with gradual elevation of diffusible serum magnesium (dSMg) to 12 mg/100mL. The fraction of filtered Mg excreted (Cmg/Ccr) rose steeply as dSMg increased to 7.0 mg/100mL; with further rise in dSMg the Cmg/Ccr increased more slowly. Relationship between dSMg and Cmg/Ccr increased more slowly. Relationship between dSMg and Cmg/Ccr was not different during a rising or falling dSMg or with infusion of MgCl₂ or MgSO₄. Magnesium reabsorption increased to reach a Tm of 140 µg/in per kg body weight when filtered load was 280 µg/min per kg body weight. When factors known to decrease magnesium reabsorbtion were superimposed on MgCl2 infusioin, Cmg/Ccr was higher for any level of dSMg compared to MgCl₂ infusion alone but never exceeded unity; with acute reduction in GFR, Cmg/Ccr invariably fell and magnesium reabsorption remained unchanged. Parathyroid extract administration during MgCl₂ infusion caused a fall in Cmg/Ccr. Results indicate that 1) Magnesium excretion is determined by filtration and reabsorption without evidence of tubular secretion; 2) There is a maximum tubular reabsorptive capacity for magnesium; 3) Extracellular volume expansion produced by NaCl infusion, CaCl₂ infusion, or chronic CDA treatment are associated with a decrease in magnesium Tm; 4) Parathyroid hormone may directly enhance magnesium reabsorption.