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Diss Factsheets

Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1993.
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:
publication
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline followed
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-benzopyrone
EC Number:
208-291-8
EC Name:
5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-benzopyrone
Cas Number:
520-34-3
Molecular formula:
C16H12O6
IUPAC Name:
5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-chromen-4-one
Test material form:
solid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source: Apin Chemicals Ltd., Oxon, UK.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: around 200 g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: arabic gum
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: suspension in arabic gum.
Doses / concentrations
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
po.
Control animals:
yes, concurrent vehicle
Positive control reference chemical:
5-hydroxyflavone (100mg/kg po)
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, blood.
- Time and frequency of sampling: urine was collected for the 24 hr after the treatment using metabolic cages; urine samples were pooled. Blood extracts were obtained from treated rats at various times after gavage. Animals were killed at the various times after treatment and whole blood collected (3-4 ml). All the biological samples were immediately frozen at -20ºC until use.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: urine was collected for the 24 hr after the treatment using metabolic cages.
- From how many animals: number not specified, urine samples were pooled.
- Method type(s) for identification: HPLC-DAD (Perkin-Elmer, LC250, equipped with a 10 x 0.46 cm column filled with Nucleosil 5CN stationary phase, 5um; MachereyNagel, Düren, Germany), detection at 345 nm. Identification of metabolites was achieved by one and two-dimensional NMR experiments.

TREATMENT FOR CLEAVAGE OF CONJUGATES: Samples to be analyzed were incubated as such in duplicate in a 50 mM sodium phosphate buffer (pH 5.5) in the presence of 1000 units/mI of b-glucuronidase (Sigma) (final volume, 200ul) for 1 hr at 37ºC. Controls were run simultaneously under the same conditions, except for b-glucuronidase, which was replaced by the same volume of buffer. The reactions were stopped by adding 400ul of acetonitrile and centrifuged. Fifty ul of both supematants were injected and analyzed by HPLC.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
No unchanged flavonoid could be detected, while under similar conditions nearly 100% of the aglycone was recovered from control blood spiked with diosmetin. Diosmetin is rapidly metabolized to several glucuronides, probably at the level of the intestinal mucosa. The 2 main metabolites appeared within few minutes of treatment, and plateaued after 2-6h. After 24h, the metabolites were no longer detectable in circulating blood. Treatment with b-glucuronidase of both blood and urine led to the disappearance of all metabolites and to the concomitant appearance of diosmetin.
Details on excretion:
In 24h urine samples, the same four metabolites found in blood could be seen, plus an extra peak, present in control urines. Treatment with b-glucuronidase of both blood and urine led to the disappearance of all metabolites and to the concomitant appearance of diosmetin.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
At least 4 metabolites with spectra fitting flavonoid structures, (not present in controls) could be isolated from the blood samples: 4 glucuronides were found, the main two metabolites being diosmetin 3'-glucuronide, and a diosmetin diglucuronide.

Applicant's summary and conclusion

Conclusions:
Diosmetin is rapidly metabolized to several glucuronides, probably at the level of the intestinal mucosa, inmmediately after administration. Four metabolites (diosmetin glucuronides) appear in blood within few minutes and plateau at 2-6h, and are eliminated within 24h. The same metabolites can be found in urine after 24h.
Executive summary:

A study of the metabolic fate of diosmetin after oral administration was performed on male Sprague-Dawley rats, following basic scientific principles (no GLP). Based on the results obtained, it can be stated that diosmetin is rapidly metabolized to several glucuronides, probably at the level of the intestinal mucosa, inmmediately after administration. Four metabolites (diosmetin glucuronides) appear in blood within few minutes and plateau at 2-6h, and are eliminated within 24h. The same metabolites can be found in urine after 24h.