Effect of codeine on CYP450 isoform activity of rats

Figures & data

Figure 1. UPLC-MS/MS chromatograms, blank plasma spiked with midazolam, tolbutamide, metroprolol, bupropion, phenacetin and diazepam (IS).

Figure 2. The pharmacokinetic profiles of bupropion, metroprolol, phenacetin, midazolam, tolbutamide in control group and codeine group (low, medium, high) rats (n = 8).

Table 1. Pharmacokinetic parameters of probe drugs from control group and codeine group rats (mean ± SD, n = 8).

Parameters	AUC (0-t) ng/mL*h	AUC (0-∞) ng/mL *h	t1/2z h	CLz/F L/h/kg	Vz/F L/kg	Cmax ng/mL
Bupropion (CYP2B1)
Control	68.7 ± 39.4	71.0 ± 41.1	0.8 ± 0.3	174.4 ± 74.8	184.0 ± 41.4	57.6 ± 24.1
Low	294.5 ± 256.3*	306.7 ± 265.0*	1.1 ± 0.3	58.7 ± 46.3**	87.1 ± 60.9**	166.4 ± 113.3*
Medium	224.4 ± 81.5**	247.3 ± 98.4**	1.6 ± 0.6*	46.5 ± 18.6**	99.3 ± 28.1**	116.1 ± 41.3**
High	170.0 ± 45.4**	191.4 ± 61.0**	1.8 ± 0.6**	57.5 ± 20.2**	144.5 ± 56.1	90.9 ± 16.9*
Metroprolol (CYP2D1)
Control	768.5 ± 262.3	888.3 ± 314.7	8.0 ± 5.1	13.5 ± 7.8	131.7 ± 63.2	197.8 ± 65.6
Low	977.8 ± 484.9	1065.2 ± 529.6	5.0 ± 1.5	10.8 ± 4.0	72.0 ± 11.8	243.9 ± 72.2
Medium	642.4 ± 243.1	710.0 ± 259.5	7.5 ± 3.6	16.5 ± 8.8	163.9 ± 72.8	204.3 ± 47.0
High	701.2 ± 168.9	833.3 ± 253.8	9.6 ± 7.0	13.4 ± 5.8	158.6 ± 86.0	222.5 ± 45.5
Phenacetin (CYP1A2)
Control	1649.2 ± 662.8	1658.2 ± 662.7	1.5 ± 0.5	7.2 ± 3.6	16.4 ± 10.6	2967.2 ± 899.2
Low	1979.4 ± 1267.0	1992.7 ± 1266.8	1.4 ± 0.5	7.3 ± 5.0	15.0 ± 10.0	3025.8 ± 1456.5
Medium	2163.0 ± 1339.3	2178.8 ± 1337.1	1.3 ± 0.7	6.6 ± 4.5	15.1 ± 20.5	2542.0 ± 1567.8
High	2197.0 ± 780.3	2204.0 ± 778.0	1.2 ± 0.4	5.0 ± 1.4	8.8 ± 4.2	3438.6 ± 1244.9
Midazolam (CYP3A2)
Control	16559.4 ± 1541.1	18827.3 ± 3083.7	7.4 ± 3.6	0.054 ± 0.009	0.552 ± 0.169	1108.1 ± 113.0
Low	18299.6 ± 1854.6	18990.4 ± 1710.4	4.8 ± 0.9	0.053 ± 0.005	0.368 ± 0.083*	1708.0 ± 395.5*
Medium	18352.5 ± 2074.6	21189.1 ± 3100.1	8.4 ± 2.2	0.048 ± 0.007	0.570 ± 0.113	1511.0 ± 476.5
High	17933.0 ± 4145.6	19414.2 ± 4406.4	6.3 ± 2.0	0.055 ± 0.018	0.473 ± 0.131	1294.7 ± 304.2
Tolbutamide (CYP2C11)
Control	16559.4 ± 1541.1	18827.3 ± 3083.7	7.4 ± 3.6	0.054 ± 0.009	0.552 ± 0.169	1108.1 ± 113.0
Low	18299.6 ± 1854.6	18990.4 ± 1710.4	4.8 ± 0.9	0.053 ± 0.005	0.368 ± 0.083*	1708.0 ± 395.5*
Medium	18352.5 ± 2074.6	21189.1 ± 3100.1	8.4 ± 2.2	0.048 ± 0.007	0.570 ± 0.113	1511.0 ± 476.5
High	17933.0 ± 4145.6	19414.2 ± 4406.4	6.3 ± 2.0	0.055 ± 0.018	0.473 ± 0.131	1294.7 ± 304.2

(Codeine group was compared with the control group, *p < 0.05, **p < 0.01).

Table 2. Biochemical results in rat serum after intragastric administration of codeine in the fourteenth day (mean ± SD, n = 8).

Group	Alanine aminotransferase (ALT)	Albumin (ALB)	Aspartate aminotransferase (AST)	Alkaline phosphatase (ALP)	Creatinine (Cr)	uric acid (UA)
Control	39	23	180	165	36	80
Low	60	26	430*	134	38	293**
Medium	76**	25	491**	153	33	245*
High	57*	27	368*	181	38	273*

Compared control group with alprazolam treated group (4, 8, 16 mg/kg, low, medium, high),

* p < 0.05 and **p < 0.01, as indicated by the statistical analysis T-test.