Registration Dossier

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:
other: Although the study was not conducted according to the recommended guidelines, it provides scientific valid information to assess the excretion of the substance.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1985

Materials and methods

Objective of study:
excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Renal excretion of intravenously infused ampicillin was determinated. The test substance was given as single 20 min i.v. infusions in doses ranging from 1.9 to 2.8 g to nine healthy volunteers using a cross-over design. Plasma and urinary concentrations were determined by a selective liquid chromatographic method using frequent sampling up to 10 and 30 h respectively after termination of the infusion.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Ampicillin
- Lot/batch No.: EL 101
- Other:
Supplier: Astra Lakemedel AB
Radiolabelling:
no

Test animals

Species:
human
Sex:
male
Details on test animals and environmental conditions:
- Age at study initiation: 29.4 years (mean)
- Weight at study initiation: 74.7 (mean)
- Fasting period before study: All subjects fasted for a minimum of 8 h from midnight to drug administration, except for 300 mL of water taken 30 min prior to drug administration to ensure diuresis.
- Diet (e.g. ad libitum)/ Water (e.g. ad libitum): They were required to continue fasting for three hours after drug ingestion, with the exception of 0.75 L of water (or juice etc) taken during this time.

Administration / exposure

Route of administration:
intravenous
Vehicle:
physiological saline
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Immediately before administration amoxycillin was dissolved in isotonic saline. Two butterfly cannulas were inserted into the forearm veins, one on each arm. The infusion was given in one arm and the samples taken from the other. A 3 g dose was given by use of an intravenous infusion set (Mini-set) and an infusion pump (AGA-NAC 601) over exactly 20 min (5 mL/min). The remaining infusion fluid was analysed for its content of ampicillin by h.p.l.c. in order to calculate the exact dose given.
Duration and frequency of treatment / exposure:
The subjects received the two doses according to a randomized, two-way cross-over design with an interval of 1 week between the infusions.
Doses / concentrations
Remarks:
Doses / Concentrations:
A 3 g dose was given over exactly 20 min (5 mL/min).
No. of animals per sex per dose:
9 men
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, plasma.

- Time and frequency of sampling:
The subjects were recumbent during the infusion and until the 75 min samples were taken.
Blood: blood samples were taken by the 'heparin-lock' technique during the first sampling hour, after which direct puncture using heparinized Venoject® tubes were used. Samples (10 mL) were drawn just prior to dosing and at 0, 5, 16, 15, 20, 30, 45, 75 and 105 min, and 2.5, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 10.5 h after termination of the infusion. Plasma was quickly separated by centrifugation and filtration (Sera-Clear® filters). The samples were frozen within 20 min of collection and were kept frozen at -70°C until assayed.
Urine: Urine was collected at 0-0.5, 0.5-1, 1- 1.5, 1.5-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9- 10, 10-11, and 11-12 h. Additional 1 h urine collections were taken between 22 and 30 h after the infusion. The total volume collected during each interval was recorded and an aliquot was frozen (-70°C) for assay.

Statistics:
Non-parametric signed rank methods were used. The Hodges-Lehmann estimator and Tukey confidence interval based on Wilcoxon's distribution-free signed rank test were used to estimate the results (Hollander & Wolfe, 1973). A linear regression line of renal clearance on the mid-point plasma concentration was calculated for each subject. The overall slope was estimated as the mean for the individual subjects. The hypothesis of a zero slope was tested, using approximate normal theory.

Results and discussion

Main ADME results
Type:
excretion
Results:
The mean fraction of the dose excreted unchanged in the urine was about 80%.

Toxicokinetic / pharmacokinetic studies

Details on excretion:
The mean fraction of the dose excreted unchanged in the urine was about 80%. Thus the kidney is the major route of elimination of ampicillin. The total renal clearance in all subjects exceeded the clearance by filtration. Thus the mean (s.d.) net tubular secretion of ampicillin was 49 (10) % of total renal clearance.
In five subjects, the urinary excretion rate was proportionally higher at points of time up to, 0.75 h postinfusion with plasma concentrations above 50-100 mg/L. The regression lines of the urinary excretion rate on the plasma concentration at the mid-point of the urinary sampling interval had a correlation coefficient of 0.91 to 1.00. There was no evidence of concentrationdependent renal clearance in any of the sampling intervals when renal clearance was plotted against the mid-point plasma concentration. The renal clearance was essentially unchanged over the whole plasma concentration range for ampicillin in all subjects, although the values were somewhat scattered in some subjects. The mean slope of the individual regression lines was not significantly different from zero.
The mean (s.d.) renal clearances of ampicillin was 167 (24) mL/min-1.73 m2 respectively.
The plasma clearance of ampicillin was 210 (24) mL min-1 1.73 m-2
The mean (s.d.) plasma half-life was 1.7 (0.3) h. The urinary excretion rate indicated a slower terminal disposition rate, with ampicillin half-life of 3.4 (2.0) h.
There was no apparent correlation between urine flow and renal clearance.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: Plasma: mean ampicillin half-life (s.d.): 1.7 (0.3) h
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: Urinary excretion: mean ampicillin half-life : 3.4 (2.0) h

Any other information on results incl. tables

The urinary solubility of the drugs was dependent on pH.

Applicant's summary and conclusion

Conclusions:
The mean fraction of the dose excreted unchanged in the urine was about 80%.
Executive summary:

Renal excretion of intravenously infused ampicillin was determinated. The test substance was given as single 20 min i.v. infusions in doses ranging from 1.9 to 2.8 g to nine healthy volunteers using a cross-over design.

Plasma and urinary concentrations were determined by a selective liquid chromatographic method using frequent sampling up to 10 and 30 h respectively after termination of the infusion.

The mean (s.d.) renal clearance of ampicillin was 167 (24) mL/min-1.73 m-2.

The plasma clearance of ampicillin was 210 (24) mL min-1 1.73 m-2

The mean (s.d.) plasma half-life was 1.7 (0.3) h. The urinary excretion rate indicated a slower terminal disposition rate, with ampicillin half-life of 3.4 (2.0) h.

The net secretion was about 50% of the total renal clearance of the test substance.

The mean fraction of the dose excreted unchanged in the urine was about 80%.

The renal clearance of the drug was independent of the plasma concentration.