Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Evaluation of available data.
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)

Data source

Materials and methods

Test material

Radiolabelling:
no

Administration / exposure

Details on study design:
Abacavir glutarate is the final intermediate in the synthesis of Abacavir (marketed as the hemisulphate salt), a nucleoside reverse transcriptase inhibitor for use as an antiviral agent. Abacavir glutarate has a molecular weight of 418. It is a solid at room temperature, melting at 184°C and decomposing at 227°C. Some 26% of the particles are <100 μm and 5.5% are <10.2 μm, thus significant amounts of the substance are inhalable, although most of the inhaled material is not respirable. The substance is water soluble (5.14 g/L) and is stable in solution at pH 4, 7 and 9. It has a log Pow of 1.17.
Information on the absorption, distribution and metabolism of Abacavir in humans is contained in McDowell et al. (1999). In addition there is an increase in systemic exposure with increasing oral doses to mice of Abacavir succinate over the range 250-1000 mg/kg/d for 3 days (Burnette, 1996), suggestive of substantial absorption. The absorption of glutarate has been studied in rat (e.g. Rothstein and Miller, 1952).

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Given the particle sizes of the material and its log P ow, if inhaled, it is likely that most of the administered material will be transferred to the stomach via the tracheo-bronchial escalator and swallowing.

In solution, Abacavir glutarate will be ionised into Abacavir and glutarate ions, which, in the acid milieu of the stomach will be unionised. The molecular weight, water solubility and octanol-water partition coefficient are suggestive that the substance is likely to be absorbed when administered orally. Studies in humans indicate that the Abacavir, when administered as succinate, is well (>80%) absorbed. Based on studies in rat, radiolabelled glutamic acid is also well absorbed.
Details on distribution in tissues:
The volume of distribution suggests that Abacavir is widely distributed in body water. Penetration into the cerebrospinal fluid is a required property for its efficacy. The half-life of Abacavir radioactivity (3.26 h in plasma, 5.50 h in whole blood) suggests that it is unlikely that there will be bioaccumulation, in agreement with the log Pow. Glutarate appears to be taken into intermediary metabolism.
Details on excretion:
The molecular weight suggests that parent Abacavir and polar metabolites are likely to be excreted in the urine in humans. In experimental studies, following oral administration of 600 mg 83% of the dose of radioactive Abacavir was found in urine and 16% in faeces, confirming this prediction. Of the 83% excreted in urine, 36% was excreted as the glucuronide and 30% as the carboxylic acid. Several other metabolites were present, but in quantities (<2% each) that prevented identification. Only 1.2% was excreted unchanged.

Given the molecular weight of Abacavir there may be substantial biliary excretion of Abacavir and the identified metabolites in rodents.

Glutaric acid was excreted in rats principally as exhaled carbon dioxide, with urinary metabolites including glucose, acetoacetic acid and 2-carbon fragments appearing in the urine.

Any other information on results incl. tables

Metabolism

Abacavir is metabolised to the corresponding carboxylic acid and to the glucuronide conjugate. Other metabolites are minor and have not been further identified. Glutarate probably enters intermediary metabolism, and the end point of metabolism in rat was identified as carbon dioxide.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: Bioaccumulation considered to be unlikely.
Executive summary:

Abacavir glutarate is the final intermediate in the synthesis of Abacavir (marketed as the hemisulphate salt), a nucleoside reverse transcriptase inhibitor for use as an antiviral agent. Abacavir glutarate has a molecular weight of 418. It is a solid at room temperature, melting at 184oC and decomposing at 227oC. Some 26% of the particles are <100 μm and 5.5% are <10.2 μm, thus significant amounts of the substance are inhalable, although most of the inhaled material is not respirable. The substance is water soluble (5.14 g/L) and is stable in solution at pH 4, 7 and 9. It has a log Pow of 1.17.

 

Information on the absorption, distribution and metabolism of Abacavir in humans is contained in McDowell et al. (1999). In addition there is an increase in systemic exposure with increasing oral doses to mice of Abacavir succinate over the range 250-1000 mg/kg/d for 3 days (Burnette, 1996), suggestive of substantial absorption. The absorption of glutarate has been studied in rat (e.g. Rothstein and Miller, 1952).

 

Absorption 

Given the particle sizes of the material and its log P ow, if inhaled, it is likely that most of the administered material will be transferred to the stomach via the tracheo-bronchial escalator and swallowing.  

 

In solution, Abacavir glutarate will be ionised into Abacavir and glutarate ions, which, in the acid milieu of the stomach will be unionised. The molecular weight, water solubility and octanol-water partition coefficient are suggestive that the substance is likely to be absorbed when administered orally. Studies in humans indicate that the Abacavir, when administered as succinate, is well (>80%) absorbed. Based on studies in rat, radiolabelled glutamic acid is also well absorbed.

 

Distribution

The volume of distribution suggests that Abacavir is widely distributed in body water. Penetration into the cerebrospinal fluid is a required property for its efficacy. The half-life of Abacavir radioactivity (3.26 h in plasma, 5.50 h in whole blood) suggests that it is unlikely that there will be bioaccumulation, in agreement with the log Pow. Glutarate appears to be taken into intermediary metabolism.

 

Metabolism

Abacavir is metabolised to the corresponding carboxylic acid and to the glucuronide conjugate. Other metabolites are minor and have not been further identified. Glutarate probably enters intermediary metabolism, and the end point of metabolism in rat was identified as carbon dioxide.

Excretion

The molecular weight suggests that parent Abacavir and polar metabolites are likely to be excreted in the urine in humans. In experimental studies, following oral administration of 600 mg 83% of the dose of radioactive Abacavir was found in urine and 16% in faeces, confirming this prediction. Of the 83% excreted in urine, 36% was excreted as the glucuronide and 30% as the carboxylic acid. Several other metabolites were present, but in quantities (<2% each) that prevented identification. Only 1.2% was excreted unchanged.

 

Given the molecular weight of Abacavir there may be substantial biliary excretion of Abacavir and the identified metabolites in rodents.

 

Glutaric acid was excreted in rats principally as exhaled carbon dioxide, with urinary metabolites including glucose, acetoacetic acid and 2-carbon fragments appearing in the urine.