Enzyme kinetic parameters for ertugliflozin glucuronide metabolite (M5a and M5c) formation in pooled HLMs
Data are expressed as the means ± S.D. from triplicate experiments, except M5c formation with 2% BSA (n = 6).
| Incubation conditionsa | Km | Km,ub | Vmax | Ksi | CLint,u | CLint,sc,u | fCL,UGT |
|---|---|---|---|---|---|---|---|
| µM | µM | pmol·min−1·mg−1 | µM | µl·min−1·mg−1 | ml·min−1·kg−1 | ||
| HLMs with 2% BSA | |||||||
| M5a | 379 ± 11 | 41.7 | 94.9 ± 1.2 | — | 2.28 | 2.15 | 0.06 |
| M5c | 98.3 ± 6.1 | 10.8 | 375 ± 7 | — | 34.7 | 32.8 | 0.94 |
| Total | — | — | — | — | 37.0 | 35.0 | 1.00 |
| HLMs without BSA | |||||||
| M5ac | 3130 ± 1620 | 1690 | 734 ± 363 | 86.8 ± 46.8 | 0.434 | 0.410 | 0.05 |
| M5c | 77.5 ± 3.1 | 41.9 | 384 ± 4 | — | 9.16 | 8.66 | 0.95 |
| Total | — | — | — | — | 9.59 | 9.07 | 1.00 |
↵a HLM incubations were conducted in the presence and absence of 2% BSA as described under Materials and Methods.
↵b Ertugliflozin unbound fraction (fu,inc) in HLMs (0.25 mg/ml) without BSA and with 2% BSA was 0.54 and 0.11, respectively.
↵c Apparent Km values exceeded the highest ertugliflozin concentration in incubation (1000 µM) due to substrate inhibition kinetics.