Registration Dossier

Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

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:
review article or handbook
Title:
Nonlinear Kinetics of the Thiamine Cation in Humans: Saturation of Nonrenal Clearance and Tubular Reabsorption
Author:
Weber W. et al
Year:
1990
Bibliographic source:
Journal of Pharmacokinetics and Biopharmaceutics, Vol. 18, No. 6, 1990
Report date:
1990

Materials and methods

Objective of study:
other: Saturation of Nonrenal Clearance and Tubular Reabsorption
Principles of method if other than guideline:
Each subject received a 5, 50, 100, or 200 mg dose of thiamine hydrochloride as a 2-min iv bolus or a 50-min infusion. Blood samples were collected at specified times over at least 2 days, and up to a period of 3 weeks post medication.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Thiamine hydrochloride
EC Number:
200-641-8
EC Name:
Thiamine hydrochloride
Cas Number:
67-03-8
Molecular formula:
C12H17N4OS.ClH.Cl
IUPAC Name:
thiamine hydrochloride
Specific details on test material used for the study:
Thiamine hydrochloride
Radiolabelling:
no

Test animals

Species:
other: Man
Details on species / strain selection:
13 healthy volunteers (6 male, 7 female) and 3 patients (2 male, 1 female) with abnormal kidney function participated in the study.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST VOLUNTEERS
- Age at study initiation: 27 - 59 years (median 38 years)
- Weight at study initiation: 50 - 80 kg (median 70 kg)
- Height: 163 - 192 cm (median 175 cm)
- Before entering the trial, medical history, physical examination and laboratory tests (haematology, biochemical status, urine analysis) of the healthy volunteers were recorded. Their baseline thiamine status were within normal range. At the beginning of the trial, formerly recognised thiamine deficiency of the included patients had been corrected. All of them were in good clinical condition.

Administration / exposure

Route of administration:
intravenous
Details on exposure:
Doses ranging from 5 to 200 mg thiamine hydrochloride were administered either as an intravenous bolus or a 50-min infusion.
Duration and frequency of treatment / exposure:
2 minutes iv bolus or 50 minute infusion
Doses / concentrationsopen allclose all
Dose / conc.:
5 other: mg
Dose / conc.:
50 other: mg
Dose / conc.:
100 other: mg
Dose / conc.:
200 other: mg
No. of animals per sex per dose / concentration:
13 healthy volunteers (6 male, 7 female)
3 patients (2 male, 1 female) with abnormal kidney function participated in the study.
Details on dosing and sampling:
Each subject received a 5, 50, 100, or 200 mg dose of thiamine hydrochloride as a 2-min iv bolus or a 50-min infusion. Blood samples were collected at specified times over at least 2 days, and up to a period of 3 weeks post medication. Plasma was separated and frozen until analysis. Urine collections were made half hourly over the first 2 hours, hourly until the 7th hour, and afterwards in half daily and daily intervals for up to 3 weeks. Volumes were recorded and aliquots were frozen until assayed.

Results and discussion

Applicant's summary and conclusion

Conclusions:
Total clearance, defined as the reciprocal of the area under the unit impulse response function, was found to depend on dose and creatinine clearance, as shown by a multiple nonlinear regression analysis.
The nonrenal component of the total clearance was demonstrated to be dose-dependent, whereas its mean renal component was only dependent on creatinine clearance.
At high plasma concentrations, renal clearance approached renal plasma flow, and remained constant during the decline to near physiological plasma levels. With further decline under a characteristic threshold concentration, renal clearance decreased far below the glomerular filtration rate, indicating tubular reabsorption. Binding to plasma proteins was excluded by ultrafiltration experiments. The process of renal excretion can be described by a combination of glomerular filtration, flow-dependent tubular secretion, and saturable tubular reabsorption. The concentration dependency of renal clearance was reflected in its mean value, which was only 76% of its maximum value measured in the higher concentration range. In the dose range studied, most of the given dose had already been linearly excreted before tubular reabsorption became evident, and consequently the measured mean renal clearances did not differ enough from one another to exhibit the expected dose dependency.

With increasing dose a shift of the cleared dose fraction from the non renal to the renal side was observed. Saturated non renal clearance alone could explain this effect.
Executive summary:

The pharmacokinetics of thiamine in plasma and urine was investigated in 13 healthy and 3 renal-insufficient volunteers.

Doses ranging from 5 to 200 mg thiamine hydrochloride were administered either as an iv bolus or a 50-min infusion.

A sum of 3 exponentials was used as the unit impulse response function to characterize plasma kinetics. Drug input was mathematically described as a rectangular pulse of length 2 or 50 min. Total clearance, defined as the reciprocal of the area under the unit impulse response function, was found to depend on dose and creatinine clearance, as shown by a multiple nonlinear regression analysis. The nonrenal component of the total clearance was demonstrated to be dose-dependent, whereas its mean renal component was only dependent on creatinine clearance. At high plasma concentrations, renal clearance approached renal plasma flow, and remained constant during the decline to near physiological plasma levels.  With further decline under a characteristic threshold concentration, renal clearance decreased far below the glomerular filtration rate, indicating tubular reabsorption. Binding to plasma proteins was excluded by ultrafiltration experiments. The process of renal excretion can be described by a combination of glomerular filtration, flow-dependent tubular secretion, and saturable tubular reabsorption. The concentration dependency of renal clearance was reflected in its mean value, which was only 76% of its maximum value measured in the higher concentration range. In the dose range studied, most of the given dose had already been linearly excreted before tubular reabsorption became evident, and consequently the measured mean renal clearances did not differ enough from one another to exhibit the expected dose dependency. With increasing dose a shift of the cleared dose fraction from the non renal to the renal side was observed. Saturated non renal clearance alone could explain this effect.

Categories Display