TABLE 2

Pharmacokinetic variables of repaglinide and its metabolites M1, M2, and M4 after a single oral dose of 0.25 mg of repaglinide in 10 healthy volunteers, when repaglinide was administered 1 h after placebo (control) or a single dose of 30, 100, 300, or 900 mg of gemfibrozil

Values are mean ± S.D.

Variable	Control	Gemfibrozil Dose
Variable	Control	30 mg	100 mg	300 mg	900 mg
Repaglinide
C_max (ng/ml)	4.3 ± 1.2	5.6 ± 1.1^*	6.9 ± 1.9^**^{,^†}	8.8 ± 2.5^***^{,^††,^‡}	9.6 ± 2.2^***^{,^†††}
Fold (range)		1.4 (0.8–2.2)	1.7 (1.0–2.4)	2.1 (1.3–3.0)	2.4 (1.4–3.2)
T_max (min)	30 (30–45)	37.5 (30–45)	45 (30–100)^†	37.5 (30–80)	37.5 (30–60)
t_1/2 (h)	1.5 ± 0.2	1.8 ± 0.3^*	1.9 ± 0.3^***	2.4 ± 0.4^***^{,^†,^‡‡‡}	3.1 ± 0.6^***^{,^†††,^‡‡‡,^¶¶}
Fold (range)		1.2 (0.9–1.7)	1.2 (0.9–1.4)	1.6 (1.1–2.0)	2.0 (1.4–2.9)
AUC_{0–9 h} (ng · h/ml)	4.7 ± 1.0	8.1 ± 2.1^***	20.2 ± 7.4^***^{,^†††}	28.7 ± 8.9^***^{,^†††,^‡‡‡}	33.1 ± 8.4^***^{,^†††,^‡,^¶}
Fold (range)		1.8 (1.1–2.3)	4.3 (2.2–6.5)	6.2 (3.1–8.0)	7.2 (4.9–9.8)
AUC_0-∞ (ng · h/ml)	4.7 ± 1.0	8.3 ± 2.3^***	21.2 ± 8.0^***^{,^†††}	31.5 ± 10.4^***^{,^†††,,^‡‡‡}	38.8 ± 11.4^***^{,^†††,^‡‡‡,^¶¶}
Fold (range)		1.8 (1.1–2.4)	4.5 (2.2–6.9)	6.7 (3.3–8.8)	8.3 (5.6–11.4)
M1
C_max (ng/ml)	0.16 ± 0.06	0.17 ± 0.05	0.18 ± 0.07	0.24 ± 0.07^**^{,^†,^‡}	0.27 ± 0.07^***^{,^†††,^‡}
Fold (range)		1.2 (0.6–2.1)	1.2 (0.5–2.3)	1.6 (1.0–2.6)	1.8 (1.1–2.7)
T_max (min)	52.5 (30–120)	45 (30–60)	45 (30–120)^†	45 (30–100)	60 (30–120)
t_1/2 (h)	0.80 ± 0.16	0.9 ± 0.4	1.8 ± 0.5^***^{,^†††}	1.9 ± 0.4^***^{,^†††}	2.5 ± 0.4^***^{,^†††,^‡‡‡,^¶¶¶}
Fold (range)		1.2 (0.7–2.2)	2.3 (1.2–3.8)	2.5 (1.3–3.9)	3.2 (2.1–4.8)
AUC_{0–9 h} (ng · h/ml)	0.26 ± 0.08	0.29 ± 0.08	0.49 ± 0.17^***^{,^†††}	0.75 ± 0.23^***^{,^†††,^‡‡}	1.04 ± 0.25^***^{,^†††,^‡‡‡,^¶¶}
Fold (range)		1.2 (0.6–1.7)	2.0 (0.9–3.2)	3.1 (2.0–7.2)	4.2 (2.6–5.7)
AUC_0-∞ (ng · h/ml)	0.27 ± 0.07	0.31 ± 0.08	0.55 ± 0.19^***^{,^†††}	0.80 ± 0.24^***^{,^†††,^‡‡}	1.16 ± 0.28^***^{,^‡‡‡,^¶¶}
Fold (range)		1.2 (0.6–1.6)	2.0 (1.0–3.0)	3.1 (2.1–6.8)	4.4 (2.8–5.6)
M1/repaglinide AUC_{0–9 h} ratio	0.06 ± 0.02	0.04 ± 0.01^**	0.03 ± 0.02^***^{,^†}	0.03 ± 0.01^***^{,^†}	0.03 ± 0.01^***
Fold (range)		0.7 (0.3–1.0)	0.5 (0.2–0.8)	0.5 (0.3–0.9)	0.6 (0.5–0.8)
M2
C_max (ng/ml)	0.15 ± 0.06	0.12 ± 0.04	0.09 ± 0.05^***^{,^††}	0.09 ± 0.03^**^{,^†}	0.11 ± 0.06^*^{,^‡}
Fold (range)		0.9 (0.5–1.5)	0.6 (0.3–0.8)	0.6 (0.4–1.2)	0.8 (0.5–1.2)
T_max (min)	45 (30–80)	52.5 (30–100)	60 (30–100)	45 (30–100)	45 (30–100)
t_1/2 (h)	0.9 ± 0.5	0.8 ± 0.2	2.0 ± 1.1^**^{,^†}	2.4 ± 1.1^*^{,^††}	2.1 ± 0.8^*^{,^†††}
Fold (range)		1.1 (0.3–1.8)	2.5 (1.1–5.2)	3.4 (0.5–5.9)	2.9 (0.5–5.0)
AUC_{0–9 h} (ng · h/ml)	0.24 ± 0.08	0.24 ± 0.09	0.23 ± 0.09	0.25 ± 0.06	0.35 ± 0.20^*^{,^‡}
Fold (range)		1.1 (0.6–1.9)	1.1 (0.5–1.6)	1.1 (0.8–1.5)	1.5 (0.8–2.8)
AUC_0-∞ (ng · h/ml)	0.25 ± 0.07	0.25 ± 0.09	0.28 ± 0.08	0.30 ± 0.07^*^{,^†}	0.41 ± 0.21^*^{,^†}
Fold (range)		1.0 (0.6–1.7)	1.2 (0.5–1.7)	1.2 (0.9–1.7)	1.6 (1.0–3.0)
M2/repaglinide AUC_{0–9 h} ratio	0.05 ± 0.02	0.03 ± 0.01^**	0.01 ± 0.01^***^{,^†††}	0.01 ± 0.004^***^{,^†††,^‡}	0.01 ± 0.01^***^{,^†††}
Fold (range)		0.6 (0.3–1.2)	0.3 (0.1–0.5)	0.2 (0.1–0.3)	0.2 (0.1–0.3)
M4
C_max (U/ml)	3.5 ± 1.4	3.3 ± 1.5	1.9 ± 1.6^**^{,^†††}	1.1 ± 1.3^***^{,^†††}	< 0.5
Fold (range)		1.0 (0.5–1.4)	0.5 (0.1–1.0)	0.3 (0.1–0.8)
AUC_{0–9 h} (U · h/ml)	5.5 ± 1.2	5.8 ± 1.6	4.4 ± 2.3^†	3.0 ± 1.2^***^{,^†††,^‡}
Fold (range)		1.0 (0.7–1.3)	0.8 (0.4–1.3)	0.5 (0.3–0.9)
AUC_{0–3 h} (U · h/ml)	4.0 ± 1.2	4.2 ± 1.5	2.7 ± 2.2^*^{,^†}	1.5 ± 1.2^***^{,^†††}
Fold (range)		1.0 (0.6–1.4)	0.6 (0.02–1.3)	0.4 (0.1–0.8)
M4/repaglinide AUC_{0–9 h} ratio	1.2 ± 0.3	0.76 ± 0.29^***	0.26 ± 0.18^***^{,^†††}	0.12 ± 0.10^***^{,^†††,^‡}
Fold (range)		0.62 (0.41–1.03)	0.20 (0.09–0.49)	0.10 (0.04–0.29)
M4/repaglinide AUC_{0–3 h} ratio (U/ng)	1.0 ± 0.3	0.66 ± 0.27^**	0.23 ± 0.21^***^{,^†††}	0.11 ± 0.12^***^{,^†††,^‡}
Fold (range)		0.66 (0.35–1.14)	0.22 (0.06–0.60)	0.11 (0.03–0.39)

AUC_0-∞, area under the plasma concentration-time curve from time 0 to infinity.
* P < 0.05 vs. control;
** P < 0.005 vs. control;
*** P < 0.001 vs. control;
† P < 0.05 vs. 30 mg;
†† P < 0.005 vs. 30 mg;
††† P < 0.001 vs. 30 mg;
‡ P < 0.05 vs. 100 mg;
‡‡ P < 0.005 vs. 100 mg;
‡‡‡ P < 0.001 vs. 100 mg;
¶ P < 0.05 vs. 300 mg;
¶¶ P < 0.005 vs. 300 mg;
¶¶¶ P < 0.005 vs. 300 mg.