Pentanedioic acid, compd. with (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (1:1)

Endpoint summary

Description of key information

An expert assessment of all available information on the reference substance, it's analogues and metabolites has provided the following conclusions.

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).

A further two studies performed on an analogue substance concluded as follows:

Ravitch & Brouwer 1997:  

Oral administration of the test material to pregnant New Zealand White rabbits throughout organogenesis at doses of 125, 350 or 700 mg/kg/day

(62.5,175 or 350 mg/kg, given twice daily) was associated with:

∙ Maternal toxicity at 700 mg/kg/day

∙ Cmax and AUC increased with dose

 

Burnette 1996: Plasma levels of the test material in mice at 30 min post-dose on dose day 3 of this study indicated increased systemic exposure to the test material with increasing oral doses of the test material over the tested dose range (250 to 1000 mg/kg/day).

Additional information

The TK assessment (1997) has been based on all available information and therefore can be considered to be the key endpoint for the purposes of this assessment.

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.