Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans

Figures & data

Table 1. In vitro activity of bexagliflozin and its principal human metabolites.

Compound	Structure	SGLT2 IC50 (nM)
Bexagliflozin (EGT0001442)		2.3
EGT0001301		428
EGT0001494		93
EGT0001684 [(S)-EGT0001663]		17.9
EGT0001685 [(R)-EGT0001663]		291
EGT0002147		16,200
EGT0002148		4060
EGT0002149		7730

EGT0001684 and EGT0001685 are stereoisomers not resolved by the chromatographic conditions used for sample analysis and are collectively referred to elsewhere in the text as EGT0001663 to reflect this circumstance.

Table 2. Distribution of radiolabel among parent compound and metabolites in rats, monkeys and humans.

Analyte	Rat			Monkey			Human
	Plasma	Urine	Faeces	Plasma	Urine	Faeces	Plasma	Urine	Faeces
All ^14C		14.4	86.6		29.2/41.4	54.1		40.5	51.1
Bexagliflozin	73–86	3.5	61.5	63–76	12.3	33	55.3	1.5	28.7
EGT0001301	<4	0.3	10.4			8.7–9.7	2.30	1.7	8.0
EGT0001494	4–8	8.4	6.1	7–9	11.1	6.0–6.5	3.75	3.9	10.1
EGT0001663	<2	0.9	3.5		3.2	0.5	1.73		1.1
EGT0002147							1.33	1.6
EGT0002148							0.66	0.5
EGT0002149							17.8	30.1
VM1				5–10		3.2–4.3
VM2		0.7
VM3				4–5
VM7			4.3		1.8
VM11	2–11
HM1								0.15
HM2									0.12

Shown are the percentage of total administered radioactivity recovered as the indicated compound in excreta, or the fraction of plasma radioactivity. Plasma column entries sum to ∼100%, whereas urine and faeces column entries sum to approximately the percentage of input label in the top row (all ¹⁴C). Rat recovery exceeded 100%, and monkey urine contained 41.4% of input label if cage wash counts were included. Glucuronide standards were not available at the time of the rat and monkey studies.

Table 3. Relative proportions of metabolites in male and female cynomolgus monkeys.

Analyte	Male	SD	Female	SD
Bexagliflozin	100		100
EGT0001301	4.8	1.9	4.9	1.2
EGT0001494	17.6	3.4	18.6	4.2
EGT0001663	4.6	1.3	4.3	0.6
EGT0002147	4.8	2.0	2.6	0.9
EGT0002148	3.0	0.7	2.5	0.6
EGT0002149	26.1	11.7	19.4	5.0

Shown are the relative exposures expressed as a percentage of AUC_0–∞ of the parent compound.

SD: Standard deviation.

Figure 1. Plasma concentration of total radioactivity in plasma, blood and as bexagliflozin in plasma as a function of time from dose administration in humans.

Table 4. Pharmacokinetic parameters for bexagliflozin and its principal metabolites in humans, as inferred by distribution of ¹⁴C-labelled material.

Analyte	Cmax, ngequiv g^-1	Tmax, h	t1/2, h	AUC0–t, ngequiv h g^-1	AUC0–∞, ngequiv h g^-1	AUC % of parent
Total ^14C	1070	1.0	6.7	4558	4816
Bexagliflozin	692	0.5	5.6	2523	2604	100
EGT0001301	28.8	1.0	2.1	105	111	4.16
EGT0001494	28.4	2.0	5.0	171	176	6.78
EGT0001663	14.2	2.0	1.9	78.9	83.7	3.13
EGT0002147	33.3	1.0	NC	60.5	NC	2.40
EGT0002148	5.10	2.0	NC	30.3	NC	1.20
EGT0002149	231	1.0	6.9	813	855	32.2

NC: Not calculated/insufficient data to estimate.

Figure 2. Representative radiochromatograms of human samples. Radiochromatograms depicting the nine discrete human specimen peaks are shown. Peak identifications: 1, metabolite HM1; 2, EGT0001301; 3, EGT0001494; 4, metabolite HM2; 5, EGT0002147; 6, EGT0001663; 7, EGT0002148; 8, EGT0002149; 9, bexagliflozin.

Figure 3. Metabolic fate of bexagliflozin in rats, monkeys and humans. The principal metabolites of the parent compound bexagliflozin in SD rats, cynomolgus monkeys and healthy human subjects are displayed above. The percentages represent the plasma AUC proportionality relative to bexagliflozin.

Figure 4. Relative disposition of bexagliflozin in human excreta. The percentages shown represent the proportion of input radioactivity recovered in the specified form.