Chiral metabolism of propafenone in rat hepatic microsomes treated with two inducers

Table 1 The amount and activity of P450 in rat liver microsomes (mean ± SD, n = 3)

Pretreat	P450 in pro/μmol•g¯¹	Extent of P450-MI complex△A	Activity of EROD/μmol•min-1μg-1
Control	0.95 ± 0.15	0.5 ± 0.2	0.22 ± 0.04
BNF	1.42 ± 0.21	2.2 ± 0.4	3.87 ± 0.20b
Dex	1.11 ± 0.17	18.3 ± 3.6a	0.18 ± 0.02

^aP < 0.01, vs BNF or control,

^bP < 0.01, vs Dex or control.

Table 2 Ratio of S (+)/R (-) propafenone at different concentrations in rat liver microsomal incubates (mean ± SD, n = 3)

Enantiomer/mg•L¯¹	Pretreat
	Control	Dex	BNF
5	1.016 ± 0.016	1.177 ± 0.062ab	1.104 ± 0.019ab
10	1.029 ± 0.012	1.103 ± 0.057	1.069 ± 0.015
20	0.995 ± 0.016	1.088 ± 0.018	1.053 ± 0.002
40	0.974 ± 0.026	1.057 ± 0.030	1.043 ± 0.000
80	0.978 ± 0.024	1.019 ± 0.017	1.027 ± 0.005
160	0.988 ± 0.012	1.003 ± 0.019	1.005 ± 0.005

^aP < 0.01, vs control;

^bP < 0.01, vs 160 mg•L¯¹.

Table 3 Ratio of S (+)/R (-) propafenone concentration in rat li ver microsomal incubates (mean ± SD, n = 3)

Group	t (incubation)/min
	0	3	8	20	30 (min)
Control	1.000	1.017 ± 0.010	0.997 ± 0.016	1.006 ± 0.012	1.016 ± 0.016
Dex	1.000	1.007 ± 0.003	1.044 ± 0.011d	1.076 ± 0.019	1.170 ± 0.050abc
BNF	1.000	1.005 ± 0.002	1.031 ± 0.012d	1.068 ± 0.023	1.094 ± 0.017ac

^aP < 0.01, vs 8 min;

^bP < 0.05, vs BNF group;

^cP < 0.01,

^dP < 0.05, vs control.

Table 4 Enzymatic parameters in propafenone enantiomer metabolism in vitro (mean ± SD, n = 3)

Pretreat	Enantiomer	Km/μmol•L¯¹	υmax/μmol•g¯¹•min-1	Clint in prot/L μmin-1•g¯¹
Control	S (+)	94 ± 7	0.72 ± 0.07	7.6 ± 0.7
	R (-)	83 ± 6	0.75 ± 0.16	8.9 ± 1.1
Dex	S (+)	118 ± 16ab	1.04 ± 0.09c	8.9 ± 0.9a
	R (-)	86 ± 11d	0.93 ± 0.06	10.9 ± 0.8b
BNF	S (+)	128 ± 14ac	1.07 ± 0.20 b	8.3 ± 0.7a
	R (-)	105 ± 6c	1.04 ± 0.15b	9.9 ± 0.9

^aP < 0.05, vs R (-)-propafenone;

^bP < 0.05,

^cP < 0.01, vs corresponding enantiomer in control;

^dP < 0.05, vs R (-)-isomer in BNF.

Table 5 The stereoselective effects of nimodipine on metabolic depletion of propafenone (mean ± SD, n = 3)

Group	Nimodipine/mg•L¯¹	S (+)-propafenone	R (-)-propafenone/mg•L¯¹	S/R
DEX	0	2.10 ± 0.04	1.75 ± 0.14a	1.20
DEX	8	2.32 ± 0.26	2.10 ± 0.21b	1.1
0DEX	16	3.81 ± 0.11c	3.62 ± 0.13c	1.0
6DEX	32	4.30 ± 0.13c	4.17 ± 0.26c	1.03

^aP < 0.01, vs S(+)-propafenone in DEX without nimodipine;

^bP < 0.05,

^cP < 0.001, vs the corresponding enantiomer in DEX without nimodipine.