(R*,S*)-(±)-α-[1-(methylamino)ethyl]benzyl alcohol hydrochloride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Animal experimental study, minor restrictions in design and/or reporting but otherwise adequate for assessment

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1977

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

Investigations were carried out with radiolabled substance to establish whether difference exist in their metabolic fate in the rabbit, in vivo and in vitro.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

(R*,S*)-(±)-α-[1-(methylamino)ethyl]benzyl alcohol hydrochloride

EC Number:

205-153-9

EC Name:

(R*,S*)-(±)-α-[1-(methylamino)ethyl]benzyl alcohol hydrochloride

Cas Number:

134-71-4

Molecular formula:

C10 H15 N O .Cl H

IUPAC Name:

(1-hydroxy-1-phenylpropan-2-yl)(methyl)azanium chloride

Details on test material:

- Name of test material (as cited in article): D(-)ephedrine and L(+)-ephedrine

Radiolabelling:

yes

Remarks:

carbinol-14C

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 1.6 - 2.5 kg
- Fasting period before study: not performed
- Housing: metabolic cages
- Individual metabolism cages: no, per 2 animals
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: room temperature

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

unchanged (no vehicle)

Details on exposure:

Animals received a combination of (±)-[cabinol-14C]ephedrine diluted with nonradioactive (±)-ephedrine (1:1.5).

Duration and frequency of treatment / exposure:

Single injection

Doses / concentrations

Remarks:

Doses / Concentrations:
3 - 5 µCi (= 3 mg/kg bw)

No. of animals per sex per dose / concentration:

6

Details on study design:

IN VITRO STUDY:
After the animals were killed by a blow on the head, the liver was excised and transferred. The microsomes were extracted and used for in vitro incubation. Incubation mixtures consisted of 5 mg of microsomal protein, 2.5 μmol of substrate, a NADPH-generating system and 150 μmol of Tris-HCI buffer, pH 7.4, in a final volume of 3.0 mL. After the addition of L(+)- or D(-)-ephedrine (0.4-0.8 µCi/mg), all flasks were transferred from ice to a Dubnoff metabolic shaker and incubated in air at 37°C with shaking (90 oscillations/min) for 15, 30, and 60 min. Aliquots of each incubation flask were either freeze-dried or transferred to scintillation vials for the quantitation of radioactivity.

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, tissues
- Time and frequency of sampling: urine and faeces 24 hr-intervals for 6 days
- From how many animals: combined from 2 animals
- Method type(s) for identification: Liquid scintillation counting

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:

IN VIVO STUDY
From both isomers, > 80% of the total 14C was excreted within 48 hr after dosing; the majority of 14C excretion (71-91%) occurred within 24 hr. Small amounts of radioactivity were detected in the urine even after 6 days. From the data presented, it was also observed that the urinary elimination of radioactivity by rabbits dosed with D(-)-ephedrine was slower than by those given L(+)-ephedrine. Although not presented, elimination of 14C in feces did not appear to be an important route; < 3% of the total 14C of the ephedrine isomers were recovered in feces within the first 48 hr.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

IN VITRO STUDY
Both isomers of ephedrine were extensively metabolized after a 1-hr incubation. D(-)-ephedrine was metabolized to a greater degree and the amounts of benzoic acid and norephedrine formed from this isomer exceeded those formed from L(+)-ephedrine. Quantitation of the metabolites by inverse isotope-dilution analysis and two-dimensional chromatography revealed that nearly all of the 14C (91-98%) was present as benzoic acid, ephedrine, and norephedrine. Unchanged ephedrine, norephedrine, 1-phenyl-1,2-propanediol, and benzoic acid represented the majority of radioactivity (90-95%) present at the various incubation times. It is clear that a) D(-)-ephedrine was more rapidly metabolized than the L(+)-isomer, b) comparable rates of nor- ephedrine and 1-phenyl-1,2-propanediol formation were observed with both isomers, and c) the rate of benzoic acid formation from D(-)-ephedrine was about three times greater than that from L(+)-ephedrine over the entire incubation period. Further, the data showed that norephedrine was the predominant metabolite formed from both ephedrine isomers and that oxidative deamination of the side chain to form benzoic acid and 1-phenyl-1,2-propancdiol constituted a major route of biotransformation for both isomers in rabbit liver microsomes.

IN VIVO STUDY
Little unchanged ephedrine, norephedrine, or 1-hydroxy-1-phenyl-2- propanone was present in the urine of rabbits dosed with either ephedrine isomer. In each case, greater amounts of these 14C-metabolites were found in the urine of animals given L(+)-ephedrine. The major 14C-metabolites of both isomers were hippuric and benzoic acids. The total amount of hippuric acid excreted from rabbits dosed with D(-)-ephedrine was greater than that from L(+)-ephedrine (30% vs. 16%). Greater amounts of hippuric acid and lesser amounts of benzoic acid were found in urine of rabbits dosed with D(-)-ephedrine. Hippuric acid accounted for about 21% and 35% of the 24-hr 14C excretion for L(+)- and D(-)-ephedrine, respectively. More 1-phenyl-1,2-propanediol, either free or conjugated, was present in the urine of rabbits receiving L(+)-ephedrine.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
These experiments indicate that the major pathway for the biotransformation of D(-)-ephedrine and L(+)-ephedrine involves N-demethylation and oxidative deamination of the side chain.

Executive summary:

Investigations were carried out with radiolabeled D(-)-ephedrine and L(+)-ephedrine to establish whether differences exist in their metabolic fate in the rabbit, in vivo and in vitro.In liver microsomal preparations, D(-)-ephedrine was metabolized at a faster rate than L(+)-ephedrine, benzoic acid was formed from D(-)-ephedrine at a rate about three times greater than from the L(+)-isomer, and the relative amounts of norephedrine and 1-phenyl-1,2-propranediol formed from both ephedrine isomers were nearly identical throughout the entire incubation period. In vivo, both ephedrine isomers were extensively metabolized and the majority of total radioactivity (71-91%) was excreted within 24 hr. A greater 14C-excretion rate was observed for L(+)-ephedrine. From an analysis of 0- to 24-hr urine, it was found that 47-50% of the urinary 14C was attributable to acidic metabolites (hippuric acid and benzoic acid) from L(+)- and D(-)-ephedrine, from 4 to 16% of the total 14C obtained with both isomers was accountable as 1-phenyl-1,2-propanediol, either free or as a glucuronide conjugate, no appreciable quantities of sulfate or glucuronide conjugates of p-hydroxylated metabolites of ephedrine or norephedrine was detectable, and small amounts (<4% of metabolites corresponding to unchanged ephedrine, norephedrine, or 1-hydroxy-l-phenyl-2- propanone were found in urine of animals given either isomer. These experiments indicate that the major pathway for the biotransformation of D(-)-ephedrine and L(+)-ephedrine involves N-demethylation and oxidative deamination of the side chain.