Octane, 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-

Endpoint summary

Description of key information

Pharmacokinetic and metabolism studies have been conducted on AC-6000 in both rats and cynomolgus monkeys following the oral administration of a single dose of 500 mg/kg by gavage. The levels in serum and in the urine of both AC-6000 and a presumed metabolite, PFHxA (2,2,3,3,4,4,5,5,6,6-6-Undecafluorohexanoic acid), were measured by GC-MS and LS MS/MS respectively.

Rats

Six male Sprague Dawley rats were given a single dose of 500 mg/kg AC-6000 by gavage. Blood samples were collected from the cervical vein of three rats for each time point at 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours after dosing and were analysed for both AC-6000 and perfluorohexanoic acid (PFHxA). The remaining rats were individually kept in metabolism cages and urine was collected over the following time periods post-dosing: 0-6; 6-12; 12-24; 24-48; 48-72 hrs. The urine samples from the three rats were also analysed for the two substances.

Levels in serum

AC-6000 was detected in the serum of three rats, 2 hours after dosing. The levels tended to increase over the next 6 hours, following which the levels fell, falling below the limit of detection for AC-6000 after 48 hours.

PFHxA was detected in the serum of two out of the three rats, two hours after dosing, and in all three rats after 4 hours. The levels increased over the next 6 hours, following which the levels fell, falling below the limit of detection for PFHxA after 48 hours.  

Levels in urine

AC-6000 was detected in the urine from one of the three rats collected during the first 6 hours after dosing. The levels were below the limit of detection for AC-6000 in urine collected from the other two rats and in urine collected from all three rats over subsequent periods.

PFHxA was detected in the urine of all three rats collected during the first 6 hours after dosing. The levels were increased in urine collected over the next 6 hours and, subsequently, over the next 12 hours. The levels declined in urine collected on Days 2 and 3 after dosing.

Monkeys

Three male cynomolgus monkeys were given a single dose of 500 mg/kg AC-6000 by gavage. Blood samples were collected from the femoral vein of each monkey at 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours after dosing and were analysed for both AC-6000 and PFHxA. The monkeys were individually kept in metabolism cages and urine was collected over the following time periods post-dosing: 0-6; 6-12; 12-24; 24-48; 48-72 hrs. The urine samples from the three monkeys were also analysed for the two substances.

Levels in serum

AC-6000 was detected in the serum of the three monkeys, 2 hours after dosing. The levels tended to increase over the next 6 hours and, in one of the three monkeys, over the subsequent 4 hours. The levels fell below the limit of detection for AC-6000 in two of the three monkeys, 8 hours after dosing and, in the remaining monkey, 12 hours after dosing.

PFHxA was detected in the serum of all three monkeys, two hours after dosing, and in two of the three monkeys after 4 hours. The levels fell below the limit of detection for PFHxA 6 hours after dosing.

Levels in urine

AC-6000 was not detected in the urine in any of the three monkeys sampled.

PFHxA was detected in the urine of all three monkeys collected during the first 24 hours after dosing. The levels of PFHxA in urine collected on day 2 and day 3 after dosing, respectively, declined. It was noted that the peak urinary levels of PFHxA measured in one monkey were one order of magnitude greater than those measured in the other two monkeys.

Comments

The oral administration of 500 mg/Kg AC-6000 to the rat yielded a peak mean serum level of only 2197 ng/ml of AC-6000 at 4 hrs after administration. The AUC for AC-6000 in the rat was calculated to be 5830 ng hr/ml. Assuming a bodyweight of 355 gm (mean bodyweight of the rats) and a blood volume of 21.3 ml (assuming 6% of body weight), the total amount of AC-6000 absorbed approximates to 125 µg, compared to a total administered dose of 177.5 mg. In the cynomolgus monkey, a peak mean serum level of 807 ng/ml AC-6000 was seen 6 hours after administration. These data suggest that AC-6000 is poorly absorbed in both the rat and the cynomolgus monkey.

In the rat, both AC-6000 and PFHxA were detected in serum two hours after the oral administration of AC-6000. The levels of both substances were higher at subsequent time points and were detectable at 24 hours following administration, both falling below the limit of detection after 48 hours, the respective levels thus mirroring each other. In the urine of the rats, however, AC-6000 was only detected in one rat and only at the two-hour time point, whereas PFHxA was detected at all time points assessed, peaking between 12 and 24 hours after the oral administration of AC-6000. These data provide evidence of the potential metabolism of AC-6000 to PFHxA in the rat. It is assumed that absorbed AC-6000 partitions from the blood to other organs, perhaps adipose tissue (log P_ow = 5.3) or even the liver, thus providing a pool for subsequent metabolism.

In the monkey, both C-6000 and PFHxA were detected in serum two hours after the oral administration of AC-6000. The levels of AC-6000 were higher at subsequent time points and were detectable in one animal at 10 hours following administration. The peak levels of PFHxA occurred at the two-hour time point and fell below the limit of detection after 24 hours in all three animals. AC-6000 was not detected in the urine of the monkeys. However, PFHxA was detected in all urine samples collected up to 72 hours post-administration, peaking in the samples collected over the first 24 hours following the oral administration of AC-6000. These data provide evidence of the potential metabolism of AC-6000 in the cynomolgus monkey. The peak urinary levels of PFHxA in one monkey were around one order of magnitude higher than those in the other two animals. This difference could be due to biological variation, but the degree of difference suggests that other factors might apply such as polymorphism in the enzyme system that is responsible for the metabolism of AC-6000.

Conclusion

The weight of evidence suggests that AC-6000 is potentially metabolised to PFHxA in both rats and cynomolgus monkeys. The exact route of metabolism is unknown and is not immediately apparent when considering its structure.