Pharmacokinetics of ligustrazine ethosome patch in rats and anti-myocardial ischemia and anti-ischemic reperfusion injury effect

Figures & data

Table 1 Scoring system of arrhythmia

Arrhythmia scores	Arrhythmia type
0	No arrhythmia
1	Atrial arrhythmia or accidental ventricular premature beat
2	Frequent ventricular premature beat
3	VT (1–2/minute)
4	VT (≥3/minute or VF)

Abbreviations: VF, ventricular fibrillation; VT, ventricular tachycardia.

Figure 1 Plasma drug concentration–time curve (Group A: intragastric ligustrazine; Group B: transdermal ligustrazine ethosome patch; Group C: conventional transdermal ligustrazine patch).

Figure 2 Drug concentration–time curve of the heart (Group A: intragastric ligustrazine; Group B: transdermal ligustrazine ethosome patch; Group C: conventional transdermal ligustrazine patch).

Figure 3 Drug concentration–time curve of the liver (Group A: intragastric ligustrazine; Group B: transdermal ligustrazine ethosome patch; Group C: conventional transdermal ligustrazine patch).

Figure 4 Drug concentration–time curve of the spleen (Group A: intragastric ligustrazine; Group B: transdermal ligustrazine ethosome patch; Group C: conventional transdermal ligustrazine patch).

Figure 5 Drug concentration–time curve of the lung (Group A: intragastric ligustrazine; Group B: transdermal ligustrazine ethosome patch; Group C: conventional transdermal ligustrazine patch).

Figure 6 Drug concentration–time curve of the kidney (Group A: intragastric ligustrazine; Group B: transdermal ligustrazine ethosome patch; Group C: conventional transdermal ligustrazine patch).

Figure 7 Drug concentration–time curve of the brain (Group A: intragastric ligustrazine; Group B: transdermal ligustrazine ethosome patch; Group C: conventional transdermal ligustrazine patch).

Figure 8 Drug concentration–time curve of the muscle (Group A: intragastric ligustrazine; Group B: transdermal ligustrazine ethosome patch; Group C: conventional transdermal ligustrazine patch).

Table 2 Pharmacokinetics parameters of three groups

Parameter	Unit	Values (Group A)	Values (Group B)	Values (Group C)
A	μg · mL^−1	143.62	49.96	16.69
A	L/h	1.70	1.31	0.67
B	μg · mL^−1	0.81	5.35	1.34
β	1/h	0.05	0.04	0.02
V/F (c)	mg/(μg · mL^−1)	0.93	2.78	6.65
T1/2α	h	0.41	0.53	1.10
T1/2β	H	1.94	18.99	29.89
K21	1/h	0.06	0.22	0.08
K10	1/h	1.33	0.21	0.19
K12	1/h	0.36	0.91	0.39
Ka	1/h	6.58	3.38	3.51
Lag time	1/h	0.07	0.02	0.04
T1/2Ka	H	0.11	0.20	0.20
Tpeak	h	0.27	0.51	0.63
Cmax	μg · mL^−1	67.12	21.05	10.58
AUC	(μg · mL^−1)*h	80.42	168.38	79.31
CL (s)	mg · h^−1/(μg · mL^−1)	1.24	0.59	1.26

Table 3 The peak concentration of ligustrazine in various tissues (μg/mL or μg/g)

Group	Plasma	Heart	Liver	Spleen	Lung	Kidney	Brain	Muscle
A	77.6	82.1	136.0	130.7	73.2	68.9	101.8	78.1
B	52.2	43.4	66.2	62.9	39.3	32.2	49.0	37.1
C	17.6	22.1	31.5	29.1	17.4	14.1	22.1	19.0

Figure 9 Comparison of area under the drug concentration–time curve (AUC) in various tissues of Group A, B, and C (Group A: intragastric ligustrazine; Group B: transdermal ligustrazine ethosome patch; Group C: conventional transdermal ligustrazine patch).

Table 4 Hemorheological indices

Item	Blank control group	Ischemic control group	Ethosome patch group	Introderm TTS group
Whole blood viscosity (high shear)	4.56 ± 0.96	5.94 ± 0.94a	5.19 ± 0.78c	5.58 ± 0.74b
Whole blood viscosity (middle shear)	5.80 ± 1.14	7.30 ± 1.21a	6.45 ± 0.95c	6.84 ± 1.00c
Whole blood viscosity (low shear)	9.13 ± 2.08	13.83 ± 2.73a	11.43 ± 1.90c	12.68 ± 2.44c
Plasma viscosity	0.97 ± 0.07	1.40 ± 0.10a	1.08 ± 0.05c	1.21 ± 0.08c
hematocrit	5.64 ± 1.24	8.32 ± 1.90a	7.00 ± 0.92c	7.65 ± 1.35b
RBC aggregation index	8.19 ± 1.71	12.17 ± 2.43a	9.89 ± 1.80c	11.37 ± 2.18c
RBC deformation index	0.49 ± 0.19	0.80 ± 0.12a	0.60 ± 0.14c	0.72 ± 0.16c

Notes: Compared with blank control group:

a P < 0.01; compared with ischemic control group:

b P < 0.05;

c P < 0.01.

Abbreviations: RBC, red blood cells; TTS, transdermal therapeutic system.

Table 5 Effects of ligustrazine and IP on reperfusion arrhythmia in anesthetized rats

Group	n	VF incidence (%)	Times of ventricular premature beat	VT duration (s)
Control	10	20	8.09 ± 6.82	10.41 ± 5.48
IP	10	0	2.28 ± 2.23a	3.40 ± 4.66b
Ethosome patch	10	0	4.05 ± 4.92	11.79 ± 8.33

Notes: Compared with control group:

a P < 0.05;

b P < 0.01.

Abbreviations: IP, ischemic preconditioning; VF, ventricular fibrillation; VT, ventricular tachycardia.

Table 6 Effects of ligustrazine and IP on arrhythmia scores and myocardial infarction scope in anesthetized rats

	Control group	IP group	Ethosome patch group
Arrhythmia scores	3.22 ± 0.54	2.05 ± 0.92b	3.15 ± 0.67
Myocardium weight in infracted area/AAR (%)	15.33 ± 7.16	6.20 ± 7.76a	10.44 ± 7.80a

Notes: Compared with control group:

a P < 0.05;

b P < 0.01.

Abbreviation: IP, ischemic preconditioning.