Optimal timing for the oral administration of Da-Cheng-Qi decoction based on the pharmacokinetic and pharmacodynamic targeting of the pancreas in rats with acute pancreatitis

Table 1 Concentrations of the 10 components of DCQD distributed in pancreatic tissues

	NG(a)	4hG(a)	12hG(a)	24hG(a)
Rhein	12.65 ± 3.7	179.15 ± 77.6a	199.89 ± 34.8	50.08 ± 17.6e
Emodin	18.68 ± 8.7	1.33 ± 0.8a	34.46 ± 10.3c	39.75 ± 12.4
Naringin	415.30 ± 17.8	19.47 ± 1.4a	32.10 ± 2.7c	269.16 ± 12.9e
Honokiol	2.38 ± 1.2	1.98 ± 0.1	19.79 ± 2.2c	4.26 ± 1.0
Magnolol	1.34 ± 0.9	0.97 ± 0.2	0.97 ± 0.2	7.51 ± 0.8e
Hesperidin	162.01 ± 34.3	34.94 ± 12.6a	24.31 ± 10.3	113.26 ± 13.8e
Naringenin	847.98 ± 76.9	858.58 ± 19.6	1077.06 ± 26.8c	262.30 ± 100.6e
Aloe-emodin	439.05 ± 179.8	89.53 ± 14.8a	502.74 ± 70.7c	501.45 ± 143.4
Chrysophanol	60.99 ± 16.4	5.16 ± 2.1a	197.29 ± 17.9c	113.43 ± 23.7e
Rheochrysidin	6.79 ± 1.2	0.55 ± 0.2a	17.92 ± 1.9c	11.67 ± 0.9e

Rats were orally administered with DCQD (10 mL/kg.BW). Pancreatic tissues were collected 24 h after a single dosage of DCQD. The concentrations of the 10 components of DCQD were determined by HPLC-MS/MS. The results are presented as the mean ± SD of μg/mg (n = 6). NG(a): the sham-operated group with the dosing time at 4 h after operation. 4hG(a), 12hG(a) and 24hG(a): rats were dosed orally with DCQD at 4 h, 12 h and 24 h, respectively, after AP induction. 4hG(a) vs NG(a):

^aP < 0.05, 12hG(a) vs 4hG(a):

^cP < 0.05, 24hG(a) vs 12hG(a):

^eP < 0.05. AP: Acute pancreatitis; DCQD: Da-Cheng-Qi decoction; HPLC-MS/MS: High-performance liquid chromatography tandem mass spectroscopy.

Table 2 Pharmacokinetic parameters of the 8 detected components of Da-Cheng-Qi decoction in plasma

Parameter	NG(a)	4hG(a)	12hG(a)	24hG(a)
Aloe-emodin
T1/2 (h)	7.5 ± 3.4	4.8 ± 1.9	7.3 ± 2.7	7.5 ± 4.3
AUC0→t (μg/mL•h)	16582.3 ± 523.7	15180.5 ± 245.3a	23266.6 ± 2848.4b	32517.8 ± 3109.6dc
MRT0→t (h)	7.0 ± 1.8	6.5 ± 1.6	7.7 ± 0.9	6.2 ± 1.3
Tmax (h)	1.22 ± 1.38	1.45 ± 0.62	2.28 ± 1.44	0.67 ± 0.30dc
Cmax (μg/mL)	4080.9 ± 2491.6	2890.5 ± 955.0	2948.2 ± 997.6	7706.6 ± 2366.7dc
Rhein
T1/2 (h)	4.7 ± 1.5	6.3 ± 1.8	6.2 ± 1.2	16.6 ± 2.1dc
AUC0→t (μg/mL•h)	27164.9 ± 1686.9	19164.9 ± 1680.3	60705.9 ± 2870.4b	35470.0 ± 1910.1dc
MRT0→t (h)	4.7 ± 1.0	6.3 ± 1.5a	7.4 ± 1.3	5.9 ± 3.2
Tmax (h)	0.7 ± 0.3	1.4 ± 0.9a	1.3 ± 0.7	1.3 ± 0.4
Cmax (μg/mL)	11033.4 ± 3248.9	3037.9 ± 1040.5a	9439.4 ± 3191.6b	9938.6 ± 3349.6d
Chrysophanol
T1/2 (h)	5.2 ± 1.7	6.8 ± 3.6	4.5 ± 0.8	6.2 ± 3.8
AUC0→t (μg/mL•h)	28925.5 ± 7837.2	20214.5 ± 1460.6a	34977.3 ± 1927.7b	23102.4 ± 1614.8c
MRT0→t (h)	5.7 ± 0.8	7.2 ± 1.7a	7.3 ± 1.0	6.2 ± 1.2
Tmax (h)	1.2 ± 0.6	3.5 ± 2.5a	1.7 ± 0.5	1.3 ± 0.5d
Cmax (μg/mL)	7708.1 ± 2234.3	2296.1 ± 7643.8a	4521.8 ± 1127.1b	4772.6 ± 1078.4d
Emodin
T1/2 (h)	8.2 ± 6.6	14.7 ± 11.7	11.7 ± 6.0	20.8 ± 19.6
AUC0→t (μg/mL•h)	1891.5 ± 1692.8	395.3 ± 159.0a	395.4 ± 82.4	391.2 ± 135.8
MRT0→t (h)	5.2 ± 1.9	8.4 ± 1.7a	9.4 ± 0.8	8.6 ± 1.9
Tmax (h)	0.6 ± 0.3	3.8 ± 3.3a	3.2 ± 2.6	0.7 ± 0.7dc
Cmax (μg/mL)	546.2 ± 496.8	37.9 ± 18.4a	34.1 ± 9.6	91.8 ± 37.4
Rheochrysidin
T1/2 (h)	6.4 ± 0.9	4.6 ± 1.9	5.4 ± 2.1	8.3 ± 2.3dc
AUC0→t (μg/mL•h)	740.2 ± 623.3	3680.6 ± 1903.0a	3489.2 ± 1354.1	1301.8 ± 420.9dc
MRT0→t (h)	5.7 ± 1.4	6.4 ± 0.9	6.3 ± 1.5	8.2 ± 1.1dc
Tmax (h)	0.9 ± 0.6	2.1 ± 1.6	1.7 ± 1.3	1.5 ± 0.6
Cmax (μg/mL)	184.7 ± 92.4	713.8 ± 201.6a	642.3 ± 211.5	155.5 ± 56.4dc
Magnolol
T1/2 (h)	8.5 ± 4.9	9.4 ± 2.8	12.2 ± 3.3	22.8 ± 7.6dc
AUC0→t (μg/mL•h)	111.4 ± 37.2	44.4 ± 14.3a	83.9 ± 27.2b	81.5 ± 25.0d
MRT0→t (h)	7.2 ± 0.9	7.9 ± 1.2	9.4 ± 1.1	8.9 ± 1.2
Tmax (h)	0.7 ± 0.3	1.3 ± 0.5∆	2.8 ± 1.4	0.6 ± 0.3dc
Cmax (μg/mL)	24.2 ± 8.6	5.8 ± 2.3∆	7.7 ± 3.6	15.3 ± 13.1dc
Naringin
T1/2 (h)	5.8 ± 1.2	4.9 ± 1.8	5.3 ± 1.4	5.5 ± 1.4
AUC0→t (μg/mL•h)	918.1 ± 106.8	4920.6 ± 310.7a	5054.4 ± 435.1	2044.1 ± 26.9dc
MRT0→t (h)	5.9 ± 1.1	6.6 ± 0.8	7.9 ± 0.6	6.9 ± 1.0
Tmax (h)	0.7 ± 0.2	1.4 ± 1.4	2.5 ± 1.2	1.8 ± 1.3
Cmax (μg/mL)	229.3 ± 195.6	724.4 ± 584.7	595.1 ± 338.9	322.9 ± 148.4
Naringenin
T1/2 (h)	7.2 ± 1.7	4.9 ± 1.1a	9.3 ± 3.6b	7.7 ± 1.3d
AUC0→t (μg/mL•h)	2705.2 ± 164.6	5795.1 ± 291.4a	3758.1 ± 250.1b	4099.2 ± 148.8dc
MRT0→t (h)	6.4 ± 1.7	7.3 ± 0.4	7.7 ± 1.2	7.9 ± 1.8
Tmax (h)	0.8 ± 0.6	2.3 ± 1.4	1.6 ± 1.3	0.6 ± 0.3d
Cmax (μg/mL)	552.9 ± 226.7	720.4 ± 165.9	543.3 ± 110.4	624.9 ± 143.7

Rats were orally dosed with DCQD (10 mL/kg.BW). Plasma samples were collected from the tails at 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after a single dosage of DCQD. The samples were assessed by HPLC-MS/MS. The pharmacokinetic parameters were processed by pharmacokinetic statistic software DAS2.0.1 and the data were obtained by statistical moment calculation. The results are presented as the mean ± SD. NG(a): the sham-operated group with the dosing time at 4 h after operation. 4hG(a), 12hG(a) and 24hG(a): rats were dosed orally with DCQD at 4 h, 12 h and 24 h, respectively, after AP induction. Compared with NG(a):

^aP < 0.05, 12hG(a) vs 4hG(a):

^bP < 0.05, 24hG(a) vs 12hG(a):

^cP < 0.05, 24hG(a) vs 4hG(a):

^dP < 0.05. AP: Acute pancreatitis; DCQD: Da-Cheng-Qi decoction; HPLC-MS/MS: High-performance liquid chromatography tandem mass spectroscopy.