TABLE 3

Effects of KTZ and α-NF on PK parameters of individual drugs and metabolites

Data were fit to a noncompartmental PK model. Values represent means ± S.D. generated from six mice.

Analyte	Treatment	C_max^{^b}	AUC_0→∞^{^c}	Extrap	t_1/2	CL/F	V_z/F
				%	h	l/h	liters
Substrate
MDZ	Control	290.8 ± 89.7	347.3 ± 91.2	10.00	0.858 ± 0.297	0.282 ± 0.080	0.357 ± 0.160
	KTZ	472.8 ± 214.9	978.2 ± 34.8***	22.17	1.26 ± 0.65	0.108 ± 0.047***	0.178 ± 0.065**
	α-NF	208.7 ± 51.3	258.0 ± 29.7	7.12	0.739 ± 0.174	0.361 ± 0.044	0.378 ± 0.070
PHE	Control	2.182 ± 0.851	613.7 ± 170.8	2.74	0.228 ± 0.055	0.803 ± 0.169	0.259 ± 0.064
	KTZ	0.775 ± 0.666^*	207.1 ± 161.5	6.31	0.213 ± 0.123	5.03 ± 5.12	1.20 ± 0.91**
	α-NF	2.167 ± 0.445	1.454 ± 0.430***	1.93	0.440 ± 0.190**	0.344 ± 0.087	0.211 ± 0.081
DXM	Control	592.8 ± 226.0	1.596 ± 0.490	39.68	1.96 ± 0.45	14.4 ± 6.2	37.7 ± 8.6
	KTZ	974.0 ± 472.0	4.011 ± 2.324**	45.32	2.36 ± 0.46	6.40 ± 4.55	19.8 ± 12.0
	α-NF	381.0 ± 147.7	1.192 ± 0.651	34.13	1.76 ± 0.54	29.7 ± 22.7	62.7 ± 34.2
DIC	Control	9.247 ± 3.762	14.68 ± 7.06	20.57	1.21 ± 0.37	0.386 ± 0.152	0.634 ± 0.260
	KTZ	20.32 ± 10.45**	52.77 ± 27.62^*	39.30	1.90 ± 0.43	0.0866 ± 0.106	0.200 ± 0.190
	α-NF	8.218 ± 4.138	9.786 ± 6.136	22.13	1.51 ± 0.86	0.553 ± 0.331	1.28 ± 0.59**
CLZ	Control	41.91 ± 11.47	45.03 ± 5.35	6.73	0.660 ± 0.237	1.12 ± 1.03	0.910 ± 0.651
	KTZ	109.5 ± 58.4**	119.5 ± 50.42**	13.2	0.767 ± 0.173	0.218 ± 0.104	0.228 ± 0.112**
	α-NF	71.29 ± 37.52	91.55 ± 30.90	7.40	0.688 ± 0.240	0.384 ± 0.216	0.329 ± 0.089
Metabolite
1′-OH-MDZ	Control	3.758 ± 0.750	10.19 ± 1.89	28.73	1.49 ± 0.22
	KTZ	2.992 ± 0.628	17.72 ± 9.03	58.95	3.70 ± 1.64^*
	α-NF	4.505 ± 0.491	13.27 ± 4.39	34.56	1.73 ± 0.53
APAP	Control	500.0 ± 69.4	529.6 ± 59.5	1.86	0.475 ± 0.097
	KTZ	381.5 ± 186.2	364.4 ± 384.3**	2.64	0.537 ± 0.087
	α-NF	362.2 ± 140.7	379.2 ± 80.1*	3.11	0.529 ± 0.116
DXO	Control	53.6 ± 19.4	87.9 ± 9.4	16.40	1.08 ± 0.45
	KTZ	25.3 ± 10.7**	61.5 ± 19.2**	30.00	1.34 ± 0.21
	α-NF	40.1 ± 14.3	56.6 ± 18.6	20.88	0.948 ± 0.33
4′-OH-DIC	Control	141.6 ± 57.5	171.5 ± 56.3	14.61	1.09 ± 0.25
	KTZ	36.4 ± 21.3^*	97.8 ± 41.3**	30.05	1.56 ± 0.17**
	α-NF^{^a}	180.8	8.4	3.20	2.10
6-OH-CLZ	Control	43.33 ± 4.62	40.7 ± 10.4	16.77	0.526 ± 0.083
	KTZ	16.47 ± 4.73***	51.4 ± 19.2	33.02	4.16 ± 1.72**
	α-NF^{^a}	5.043	7.7	66.4	1.15

Extrap, extrapolated contribution to AUC.
↵^a Given incomplete data points because some were below quantification limits, a sparse data model was used.
↵^b Values are given in nM for MDZ, DXM, APAP, DXO, 4′-OH-DIC, and 6-OH-CLZ and in µM for PHE, DIC, CLZ, and 1′-OH-MDZ.
↵^c Values are given in nM·h for MDZ, PHE (control and KTZ) APAP, DXO, 4′-OH-DIC, and 6-OH-CLZ and in µM·h for PHE (α-NF), DXM, DIC, CLZ, and 1′-OH-MDZ.
↵* P < 0.01; **P < 0.05; ***P < 0.001 compared with the control (one-way analysis of variance with Bonferroni post hoc tests).