TABLE 4

In vitro kinetic characteristics of repaglinide metabolites in pooled human hepatocytes, human liver microsomes, human S9 fractions, and recombinant P450 enzymes

Clearance estimates obtained are corrected for nonspecific binding using the estimated unbound fractions shown in Table 1. Results are expressed as mean ± S.D. (n = 3).

In Vitro System	M1			M2			M4			Glucuronide
In Vitro System	V_max^{^a}	K_m^{^b}	CLu_int^{^c}	V_max^{^a}	K_m^{^b}	CLu_int^{^c}	V_max^{^a}	K_m^{^b}	CLu_int^{^c}	V_max^{^a}	K_m^{^b}	CLu_int^{^c}
Hepatocytes	23 ± 18	58 ± 27	0.75 ± 0.96	80 ± 13	28 ± 3.8	3.3 ± 0.41	28 ± 8.5	13 ± 1.3	2.4 ± 0.56	5.7 ± 0.6	53 ± 16	0.13 ± 0.03
HLMs	170 ± 17	47 ± 3.1	4.1 ± 0.2	28 ± 5.6	24 ± 2.8	1.4 ± 0.21	130 ± 29	9.0 ± 0.72	18 ± 4.9	170 ± 9.8	37 ± 2.9	5.6 ± 0.64
S9	24 ± 1.9	58 ± 8.3	0.76 ± 0.09	94 ± 8.6	47 ± 6.4	3.7 ± 0.17	18 ± 1.4	13 ± 0.86	2.7 ± 0.15	46 ± 6.4	47 ± 13	1.8 ± 0.22
rCYP3A4	1.0 ± 0.20	8.7 ± 1.4	120 ± 29	N.D.	N.D.	N.D.	0.09 ± 0.02	47 ± 10	2.0 ± 0.14	N.A.	N.A.	N.A.
rCYP3A5	0.08 ± 0.01	66 ± 14	1.4 ± 0.31	N.D.	N.D.	N.D.	0.05 ± 0.01	≥150	0.19 ± 0.02	N.A.	N.A.	N.A.
rCYP2C8	0.08 ± 0.01	25 ± 3.8	3.7 ± 0.21	N.D.	N.D.	N.D.	0.35 ± 0.05	5.7 ± 1.2	70 ± 3.9	N.A.	N.A.	N.A.

N.D., not detectable; N.A., not applicable.
↵a Units are picomoles per minute per 10⁶ cells, picomoles per minute per milligram of protein, picomoles per minute per milligram of protein, and picomoles per minute per picomole of P450 for hepatocytes, HLMs, S9, and rP450s, respectively.
↵b Units are micromolar concentrations.
↵c Units are microliters per minute per 10⁶ cells, microliters per minute per milligram of protein, microliters per minute per milligram of protein, and microliters per minute per nanomole of P450 for hepatocytes, HLMs, S9, and rP450s, respectively.