(2R)-2-(2,4-difluorophenyl)-1,1-difluoro-1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}-3-(1H-tetrazol-1-yl)propan-2-ol

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Objective of study:

toxicokinetics

Qualifier:

no guideline required

GLP compliance:

not specified

Radiolabelling:

yes

Type:

other: absorption, distribution

Results:

Test item was absorbed and widely distributed into tissues

Type:

excretion

Results:

Test item was mainly excreted in the feces and bile; recovery of radioactivity in urine was low.

Type:

metabolism

Results:

Test item was not significantly metabolised when incubated in vitro with mouse, rat, dog, or human hepatocytes. Only 1 metabolite was detected.

Details on absorption:

Test item was absorbed widely into tissues

Details on distribution in tissues:

Test item was absorbed and widely distributed into tissues. In most tissues test item concentrations were higher than blood.

Details on excretion:

While in most tissues test item concentrations were higher than blood, test item elimination from tissues was similar to blood. Low levels of radioactivity remained in hair/fur and adrenal gland cortex at 2866 hours post-dose. The test item was mainly excreted in the feces and bile; recovery of radioactivity in urine was low.

Metabolites identified:

yes

Details on metabolites:

The test item was not significantly metabolised when incubated in vitro with mouse, rat, dog, or human hepatocytes. Only 1 possible metabolite consistent with hydroxylation and glucuronidation of the test item was detected in dog hepatocytes. No additional metabolites were detected in any of the 4 species. Furthermore, results from a metabolite screen in human plasma samples demonstrated that the sum of metabolites formed was much less than 1% of the parent concentration, thereby supporting the lack of significant metabolism in human.

In the single-dose and repeat-dose toxicity studies conducted in rats and dogs reported in the review document with the test item administered orally, blood was collected for TK analysis:

Study design		Dose	Cmax (ng/mL)	AUC (h•ng/mL)
Single-dose toxicity study in female dogs (tested doses: 30, 100, 300, or 1,000 mg/kg).		1000 mg/kg	13000	AUClast : 2680000
7-day repeated-dose toxicity study in rats (tested doses: 0, 30, 100 or 300 mg/kg/day).	Day 7	30 mg/kg/day	80100 for males 77200 for females	AUC(2-24): 1530000 for males  AUC(2-24): 1520000 for females
28-day repeated-dose toxicity study in rats (tested doses: 0, 5, 25, 60 or 120 mg/kg/day).	Day 28	5 mg/kg/day	9163 for males 12833 for females	AUC(0-24): 181520 for males AUC (0-24): 233340 for females
14-day repeated-dose toxicity study in rats (tested doses: 0, 1, 3, 5 mg/kg/day)	Day 14	3 mg/kg/day	5320 (both sexes)	AUC(0-24):111 148 (both sexes)
26-week repeated-dose toxicity study in rats (tested doses: 0, 0.15, 0.5, 1.5, or 5 mg/kg/day)	Week 26	0.5 mg/kg/day	667	AUCτ: 14500
7-day repeated-dose toxicity study in dogs (tested doses: 0, 10, 30, 100 or 300 mg/kg/day).	Day 7	30 mg/kg/day	104000 for males 43100 for females	AUC (0-24):2240000 for males AUC (0-24):944000 for females
28-day repeated-dose toxicity study in dogs (tested doses: 0, 10, 30 or 100 mg/kg/day).	Day 28	10 mg/kg/day	21100 for males 25900 for females	AUC (0-24): 473467 for males AUC (0-24): 547933 for females
39-week repeated-dose toxicity study in rats (tested doses: 0, 0.75, 2.5, 7.5, or 20 mg/kg/day)	Week 39	17 mg/kg/day	74700 (both sexes)	AUC(0-24): 1680000 (both sexes)

Conclusions:

The test item was reported to be absorbed and widely distributed into tissues. It was mainly excreted in the feces and bile; recovery of radioactivity in urine was low. It was also reported to be not significantly metabolised when incubated in vitro with mouse, rat, dog, or human hepatocytes. Furthermore, only one metabolite was detected in dogs hepatocytes.

Executive summary:

(2R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(tetrazol-1-yl)-1-[5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl]propan-2-ol was reported to be absorbed and widely distributed into tissues.While in most tissues test item concentrations were higher than blood, test item elimination from tissues was similar to blood. Low levels of radioactivity remained in hair/fur and adrenal gland cortex at 2866 hours post-dose. It was mainly excreted in the feces and bile; recovery of radioactivity in urine was low. It was also reported to be not significantly metabolised when incubated in vitro with mouse, rat, dog, or human hepatocytes. Furthermore, only one metabolite consistent with hydroxylation and glucuronidation of the test item was detected in dogs hepatocytes. No additional metabolites were detected in any of the 4 species. Results from a metabolite screen in human plasma samples demonstrated that the sum of metabolites formed was much less than 1% of the parent concentration, thereby supporting the lack of significant metabolism in human.

Description of key information

(2R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(tetrazol-1-yl)-1-[5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl]propan-2-ol was reported to be absorbed and widely distributed into tissues.While in most tissues test item concentrations were higher than blood, test item elimination from tissues was similar to blood. Low levels of radioactivity remained in hair/fur and adrenal gland cortex at 2866 hours post-dose. It was mainly excreted in the feces and bile; recovery of radioactivity in urine was low. It was also reported to be not significantly metabolised when incubated in vitro with mouse, rat, dog, or human hepatocytes. Furthermore, only one metabolite consistent with hydroxylation and glucuronidation of the test item was detected in dogs hepatocytes. No additional metabolites were detected in any of the 4 species. Results from a metabolite screen in human plasma samples demonstrated that the sum of metabolites formed was much less than 1% of the parent concentration, thereby supporting the lack of significant metabolism in human.