Registration Dossier

Toxicological information

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Pharmacokinetics of TRIS(hydroxymethyl-)aminomethane in healthy subjects and in patients with metabolic acidosis.
Author:
Brasch, H. et al.
Year:
1982
Bibliographic source:
Eur. J. Clin. Pharmacol. 22:257-264

Materials and methods

Study type:
other: study with healthy subjects and patients with metabolic acidosis
Endpoint addressed:
basic toxicokinetics
Principles of method if other than guideline:
The study was carried out to investigate the pharmacokinetics in healthy subjects and in patients with metabolic acidosis.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Analytical purity: analytical grade

Method

Type of population:
not specified
Subjects:
The subjects were 6 healthy volunteers (5 males and 1 female, aged 27 -37 years, weighing 50 -90 kg) and 20 patients in a surgical intensive care unit.
Ethical approval:
not specified
Route of exposure:
other: intravenous
Reason of exposure:
other: intentional and accidental
Exposure assessment:
not specified
Details on exposure:
Healthy volunteers:
The volunteers received TRIS 121 mg/kg (=1 mmol/kg). The 0.3 mol/L solution, titrated to pH 7.4 with HCl, was infused in 30 min in an antebrachial vein. Venous blood samples (2 mL) were collected from the other arm. The blood was centrifuged immediately and plasma and erythrocytes frozen separately until analysed. Urine was also collected.
Examinations:
- Tissues and body fluids sampled: urine, blood, haemodialysis/haemofiltration fluid, gastric juice, bile
- Time and frequency of sampling:
- blood (healthy volunteers): 10, 20, 30 min after starting the infusion; 5, 10, 20 and 40 min, 1, 2, 4, 8, 12, 20 and 24 after ending of infusion
- urine (healthy volunteers): from beginning of infusion until 30 min after its end; from 30 min to 4 h; from 4 h to 8 h; from 8 h to 24 h
- blood (patients): 20, 40, 60, 80, 100, 120 min after starting the infusion; 10, 20,40 min, 1, 2, 4, 8, 12, 18, 24 and 36 h after ending of infusion; in some patients the observation period was extended up to 72 h with further samples taken at 12 h intervals.
- urine (patients): Urine was collected for 24 h and in some cases for 1 and 2 subsequent 24 h periods.
Medical treatment:
Patients:
TRIS therapy was indicated because of metabolic acidosis with a base excess of more than 3 mmol/L. Additional medication included cardiac glycosides, sympathomimetics, low dose heparin, cimetidine, antibiotics and continuous infusions of glucose (20% or 50%) and aminoacid solutions. Generally 40 mL/kg fluid was given in 24 h. Electrolytes were administered individually according to the ionogram. The additional medication of the patients did not usually interfere with this assay, but in three patients unidentified peaks with the same retention time as TRIS appeared in the chromatogram. These cases had to be discarded from the study.
The amount of TRIS required to correct acidosis was calculated from the equation: amount of buffer (mmol) = 0.3 x base excess x body weight (kg). A 3 mol/L solution (pH 10.9) was infused via an indwelling catheter in the jugular or subclavian vein, in 2 h. Blood (1 mL) and urine samples were collected.
In cases of acute anuria haemodialysis or haemofiltration was performed once or twice a day to keep the plasma creatinine level between 300 -400 µmol/L. In a single session plasma creatinine was reduced by about 1000 µmol/L. The earliest haemodialysis was carried out 4 h after the end of the TRIS infusion.
In 2 patients gastric juice was drained continuously via a plastic tube and was collected for 48 h for TRIS analysis. In one case a T-drain had been implanted in the common bile duct during choledocholithotomy, and the drained bile was collected quantitatively over two 24 h periods.

Results and discussion

Results of examinations:
Healthy volunteers:
At the end of the infusion, the TRIS concentration in plasma averaged 565 µg/mL. There was a biexponential decline of plasma TRIS levels and after 24 h the level was only 3.8 µg/mL. TRIS concentration in erythrocytes rose more slowly, with a maximum 20 min after the end of infusion. After 2 h TRIS levels in erythrocytes were about 1.5 times those in plasma, and they remained well above the corresponding plasma levels during the rest of the observation period.
Pharmacokinetic parameters were calculated from the individual concentration-time curves using a two-compartment model with elimination from the central compartment. The volume of the central compartment was 225-279 mL/kg and the final volume of distribution was 647-1140 mL/kg. The half-life of TRIS was 3.9-9.3 h.
TRIS is mainly excreted by the kidney. Already 30 min after the end of infusion, 25% of the administered dose was found in urine and after 24 h 82% had been eliminated in this way. This was less than the total elimination of TRIS which, from the area under the curves, was calculated to be 97% during 24 h.

Effectivity of medical treatment:
Anuric patients:
A monoexponential decline of plasma TRIS levels was found in all 6 subjects. Drug concentration in erythocytes was usually higher than in plasma. The half-life ranged betwen 15 and 58 h, and the volume of distribution (418 -604 mL/kg) was only slightly larger than the volume of the central compartment in patients with two compartment kinetics (187 -563 mL/kg). 25 -66% of the infused TRIS dose left the plasma during the first 24 h, and the clearance averaged 16.7 mL/kg*h. In 5 patients repeated (2 -4) periods of haemodialysis or haemofiltration had no influence on plasma TRIS level.
Haemodialysis fluid could not be collected and TRIS concentration in haemofiltration fluid could not be determined for technical reasons (unidentified substances were eluated from the Amicon filters and produced large peaks wiht almost the same retention times as TRIS and the internal standard). Therefore, the amount of TRIS eliminated by these procedures is not known.

Normuric patients:
A biexponential decline of TRIS concentration in plasma was seen in 9 of 11 patients, and drug concentration in erythrocytes increased to about 1.5 -times the plasma level. The volume of the central compartment was 187 -563 mL/kg and the final volume of distribution was 658 -5247 mL/kg. The half-life of TRIS was 16 -45 h. In 2 patients with poor renal function (creatinine clearance: 15 mL/kg*h) TRIS plasma levels declined monoexponentially.
Up to 72% of the dose of TRIS was found in the urine after 24 h. An additional 2 -5% was excreted during the next 24 h and even in the urine of a third collection period (48 -72 h after infusion) a small amount of TRIS could be detected (1.5% of the dose). The amount of TRIS eliminated from the body, as calculated from the area under the curves, was always considerably larger than the quantity recovered from urine collection over the same time period. On average, the total body clearance of TRIS exceeded the endogenous creatinine clearance by 17.7 mL/kg*h, and there was a positive correlation beween the two parameters. In 2 patients less than 0.2% of the infused dose was found during 24 h either in gastric juice or bile.

Any other information on results incl. tables

11 patients produced normal 24 h urine volumes (610 -3480 mL) and are termed normuric in contrast to the anuric patients. However, also patients with poor renal function were included in the investigation.

It is apparent that the half-life of TRIS was much longer in the normuric patients than in healthy subjects, and that the volumes of distribution, especially the final volume of distribution, were much larger. In 2 patients of the normuric group with poor renal function (creatinine clearance: 15 mL/kg*h) TRIS plasma levels declined monoexponentially. This resembled the results obtained from the anuric patients. In anuric patients, TRIS concentration in erythocytes was usually higher than in plasma, but the difference was not as marked as in healthy subjects or nurmucic patients.

The biexponential decline of TRIS plasma levels in healthy subjects may indicate distribution to two different body compartments, one probably being extracellular water, as the volume of the central compartment equalled the volume of the extracellular space. TRIS is then taken up and accumulated inside cells, since the final volume of distribution is larger than the volume of total body water.

Applicant's summary and conclusion