Registration Dossier

Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study conducted to good scientific principles.

Data source

Reference Type:
Renal Handling of Magnesium in the Dog
Massry SG, Coburn JW & Kleeman CR
Bibliographic source:
American Journal of Physiology, 216(6): 1460-1467

Materials and methods

Objective of study:
Test guideline
no guideline followed
Principles of method if other than guideline:
Renal handling of magnesium was evaluated in 30 dogs receiving 1.0 - 3.0 µg Mg/min/kg bw with gradual elevation of diffusible serum magnesium (dSMg) to 12 mg/100 mL.
GLP compliance:

Test material

Constituent 1
Reference substance name:
Magnesium chloride
EC Number:
EC Name:
Magnesium chloride
Cas Number:
magnesium dichloride

Test animals

other: Mongrel
Details on test animals or test system and environmental conditions:
- Weight at study initiation: 12 - 27 kg

Administration / exposure

Route of administration:
other: 2.5% dextrose in water
Control animals:
not specified
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 expt 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.
Details on dosing and sampling:
Blood and urine samples were analysed for creatinine, sodium, magnesium and calcium. Water content of serum was determined by refractometry. Serum creatinine, sodium, calcium and magnesium were measured in each clearance period. Diffusible calcium and magnesium were determined in ultrafiltrates of serum. Ultrafiltrates were prepared from specimens taken during one control period and every 90 min thereafter. Percent diffusibility of calcium and magnesium was calculated as follows:

% diffusibility = (diffusible conc, mg/100 mL serum / total conc, mg/100 mL serum) x 100

The percent diffusibility of both calcium and magnesium evidenced no appreciable change in any given experiment or in the total group with the various manipulations described. Therefore, the mean percent diffusibility of calcium and magnesium in each experiment was used to calculate their diffusible fractions in those clearance periods where direct measurements were not made. The following formula was used:

Diffusible value = total conc x percent diffusibility

All clearances of calcium and magnesium are expressed in terms of their diffusible fractions.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:
The fraction of filtered Mg excreted (Clearance of diffusible magnesium [CMg] / creatinine clearance [CCr]) rose steeply as diffusible serum magnesium (dSMg) increased to 7.0 mg/100 mL; with further rise in dSMg the 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 maximal tubular reabsorptive capacity (Tm) of 140 µg/min/kg bw when filtered load was 280 µg/min/kg bw; during saline diuresis, calcium infusion or following chronic DCA treatment the Tm for magnesium was 80, 85 and 75 µg/min/kg bw. When factors known to decrease magnesium reabsorption were superimposed on MgCl2 infusion, CMg/CCr was higher for any level of dSMg compared to MgCl2 infusion alone but never exceeded unity; with acute reduction in glomerular filtration rate (GFR), CMg/CCr invariably fell and magnesium reabsorption remained unchanged. Parathyroid extract (PTE) administration during MgCl2 infusion caused a fall in CMg/CCr.

Applicant's summary and conclusion

The results of the study indicate that:

1). Mg 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 DCA treatment are associated with a decrease in magnesium Tm
4). parathyroid hormone may directly enhance magnesium absorption.