Arch. Pharm. Res. DOI 10.1007/s12272-014-0434-1

RESEARCH ARTICLE

Pharmacokinetics, tissue distribution and excretion of peimisine in rats assessed by liquid chromatography-tandem mass spectrometry Lihua Chen • Dongxun Li • Guosong Zhang • Wei Zhang • Lihua Zhang • Yongmei Guan • Weifeng Zhu • Hongning Liu

Received: 24 April 2014 / Accepted: 20 June 2014 Ó The Pharmaceutical Society of Korea 2014

Abstract Peimisine, the common ingredient of ‘‘zhebeimu’’ groups and ‘‘chuanbeimu’’ groups, is responsible for the expectorant and cough relieving effects. The aim of this study was to investigate the pharmacokinetics, tissue distribution and excretion of peimisine in male and female SD (Sprague-Dawley) rats by a rapid and sensitive LC-MS/ MS (liquid chromatography-tandem mass spectrometry) method used carbamazepine as the internal standard after oral administration, carbamazepine was stated as an IS. The results showed that peimisine was slowly distributed, and eliminated from rat plasma and manifested linear dynamics in a dose range of 0.26–6.5 mg/kg. Tested by ANOVA, there were gender differences in the pharmacokinetic parameters of AUC0-t, AUC0-? among a single dose of 0.26, 1.3, 6.5 mg/kg (P \ 0.05). Drug blood and tissue levels in male rats were significantly higher than the female counterparts after oral administration, while both the males and the females showed high drug levels in spleen, kidney, lung, liver and heart. On the other hand, the peimisine levels that can be reached in uterus, ovary, testis and brain is low. The excretion study showed that little

L. Chen (&)  W. Zhang  L. Zhang  Y. Guan  W. Zhu  H. Liu Key Laboratory of Modern Preparation of TCM, Jiangxi University of TCM, Ministry of Education, No. 18 Yun Wan Road, Nanchang 330004, People’s Republic of China e-mail: [email protected] D. Li  G. Zhang National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of TCM, Nanchang 330006, People’s Republic of China G. Zhang Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of China

administered peimisine (\0.7 %) was recovered in the male and female bile. Approximately 13.46 and 15.05 % were recovered in female urine and feces, while 43.07 and 7.49 % were recovered in male urine and feces, respectively, which indicated that the major elimination route of male rats was urine excretion. In addition, there was significant differences in total cumulative excretive ratio of peimisine in feces (P \ 0.05) and no significant differences in the urine (P [ 0.05) at a dose of 1.3 mg/kg. Keywords Peimisine  Pharmacokinetics  Tissue distribution  Excretion  Gender-related differences

Introduction Bulbus Fritillariae derived from plants of various Fritillaria species, which is the most commonly used antitussive and expectorant herb in traditional Chinese medicine (TCM) is called ‘‘Beimu’’ in China. Based on the origin and the breed, ‘‘Beimu’’ were classified into three groups: ‘‘Zhebeimu’’ groups, ‘‘Chuanbeimu’’ groups and ‘‘Tubeimu’’ groups. ‘‘Tubeimu’’ groups are bulbs of cucurbitaceae, distributed to Lung and Spleen meridian, the other two are from Liliaceae, distributed to Lung and Heart meridian (C.P. 2010). Various chemical and pharmacological studies on Beimu have demonstrated that the major biologically active ingredients present in Tubeimu are saccharide, sterol, saponin and so on (Jin et al. 2003; Liu et al. 2004), while isosteroidal alkaloids in Zhebeimu and Chuanbeimu (Gao et al. 1996; Zhang 2006). Among all the compounds found from different Fritillaria species, the major are isosteroidal alkaloids (72.7 %), the rest are steroidal alkaloids (11.5 %) and non-alkaloids (15.8 %) (Lin et al. 2001).

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Peimisine (Fig. 1), the common ingredient of ‘‘zhebeimu’’ groups and ‘‘chuanbeimu’’ groups, as well as a type of isosteroidal alkaloids (Li et al. 2006; Wagner et al. 2011), is responsible for the expectorant and cough relieving effects (Wang et al. 2011; Zhao et al. 2009), antitumor activity (Wang et al. 2014, 2014) and inhibitory potency on Angiotensin Converting Enzyme (An et al. 2010; Oh et al. 2003). Peimisine could be detected with high-performance liquid chromatography (HPLC) coupled with UV detection (Chao and Hu 1993), HPLC coupled with evaporative light scattering detection (ELSD) (Wang et al. 2011), liquid chromatography/ electrospray ionization quadrupole time-of-flight tandem mass spectrometry (LC/ESI-QTOF-MS/MS) (Zhang 2006; Zhou et al. 2010) and so on. However, low sensitivity and possible uncertainly of chromatographic peak identification (mainly by retention time) made HPLC-UV or -ELSD unlikely suitable for the routine analysis of interested peimisine, especially due to the minor level present in the plasma or tissues. On the other hand, peimisine is widely distributed in Bulbus Fritillariae, but varies in content from 0.00815 to 0.0528 % (Duan et al. 2010; Liu et al. 2010). Hence, the pharmacokinetics, tissue distribution and excretion studies of peimisine were performed by a more sensitive LC-MS-MS method we reported in 2011 (Zhang et al. 2011). In addition, the method was applied successfully to character the pharmacokinetics of peimisine in rats after oral administration of Bulbus Fritillariae Cirrhosae extract from other groups (Luo et al. 2012). Isosteroidal alkaloids might be the basis of the meridian of ‘‘zhebeimu’’ groups and ‘‘Chuanbeimu’’ groups. Hence, the pharmacokinetics, tissue distribution, metabolism and excretion studies of peimisine, especially the tissue distribution study, might be useful to explain the similarity and differences of the two groups in the pharmacological functions, as well as the meridian. However, to date, there have been no reports on the tissue distribution and excretion of peimisine monomer or related extract. Though the pharmacokinetics of peimisine after oral administration of Bulbus Fritillariae Cirrhosae was charactered (Luo et al. 2012), the pharmacokinetics of peimisine monomer even could provide useful informations to interpret the influence of other component in the extract from various species. In addition, the pharmacokinetics, tissue distribution, and excretion of peimisine in the present study were investigated in male and female rats, so as to evaluate the potential contribution of gender in some way.

Materials and methods Materials Peimisine (purity [ 99 %) and Carbamazepine (IS, purity [ 99 %) were purchased from the National Institute for

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Fig. 1 Formula of peimisine

the Control of Pharmaceutical and Biological Products (Beijing, China). Ammonium formate and acetonitrile were of HPLC grade and purchased from Sigma Company (Darmstadt, Hesse, Germany) and Merk Company (Saint Louis, MO, USA), respectively. All the other reagents were of analytical grade. Animals Sprague-Dawley (SD) rats weighing 220–250 g, were obtained from the Jiangxi University of Traditional Chinese Medicine and acclimated in the laboratory for 7 days prior to the experiments, housed with free access to food and water, on a 12 h light–dark cycle at ambient temperature (22–24 °C) and roughly 50 % relative humidity. Animal welfare and experimental procedures were in accordance with the guide for the care and use of laboratory animals and the related ethical regulations of Jiangxi University of TCM. Drug administration and sampling For pharmacokinetic study, rats were divided into four groups (6 males and 6 females, per group). Peimisine, dissolved in polyethylene glycol 400, was orally administrated at a single dose of 0.26, 1.3, 6.5 mg/kg to three groups, respectively. Then 0.25 mL blood samples were collected in heparinized eppendorf tube via the posterior orbital venous plexus before dosing and subsequently at 0.083, 0.167, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h. After centrifuging at 6,6059g for 10 min, the plasma samples were obtained and frozen at -20 °C until analysis. For tissue distribution study, five groups of rats (6 males and 6 females, per group) were orally administered a single dose of 1.3 mg/kg by the same way. Heart, liver, spleen,

Pharmacokinetics and excretion of peimisine in rats

lung, Kidney, brain, stomach, intestine, uterus, ovary, testis, fat were removed at 1, 2, 4, 6 and 8 h after dosing, respectively. Tissue samples were weighed rapidly and rinsed with physiological saline solution to remove the blood or content, then were blotted by filter paper, and at last stored at -20 °C until analysis. For biliary excretion study, twelve rats were anesthetized and a cannula was implanted into the bile duct to collect bile. Peimisine at a single dose of 1.3 mg/kg was orally administered and bile samples were collected at 0–2, 2–4, 4–8, 8–12, and 12–24 h post-dosing and stored at -20 °C after the volume of each collection was measured. For urinary and fecal excretion studies, twelve rats (6 males and 6 females) were orally administered a single dose of 1.3 mg/kg. The rats were housed in stainless-steel metabolic cages with free access to water, and food was returned approximately 4 h post-dosing. Urine and feces samples were collected at -12 to 0 h pre-dosing and 0–2, 2–4, 4–8, 8–12, 12–24 h post-dosing. The feces were dried at 45 °C for 12 h. The specimens were stored at -20 °C after the urine volume and feces dry weight for each collection period were recorded. Sample processing To a 100 lL aliquot of plasma sample, 10 lL methanol and 10 lL IS (50 ng/mL) working solution, and 20 lL ammonia water were added by turns. Samples were then vortex-mixed for 30 s in turn and extracted with 0.8 mL ethyl acetate by vortex mixing for 3 min. After centrifugation at 9,3419g for 5 min, 0.7 mL upper organic layer was transferred to another tube and evaporated to dryness at 40 °C under a gentle stream of nitrogen. The residue was reconstituted in 100 lL mobile phase (Methyl Cyanides– water: 10 mmol/L ammonium acetate, 35:65, v/v), followed by ultrasound for 10 min, vortex-mixing for 1 min and centrifugation at 18,0009g for 10 min. Finally, a

10 lL aliquot was injected into the LC-MS-MS system for analysis. All the tissues (1 g, get all if less than 1 g) homogenized in 50 % methanol–water were 1:6 (w/v), feces samples were 1:8. Then, a 0.5 g aliquot of pulverized feces sample vortexed with 4 mL 50 % methanol–water for 5 min and separated at 9,3419g for 5 min, and sampling the supernatant, finally a 200 lL of all the tissue homogenate, feces, urine and bile samples were processed further like the plasma samples. LC-MS/MS analysis and method validation Levels of peimisine in the tissue and excretion samples were analyzed by a LC-MS-MS method developed for plasma samples by our group (Zhang et al. 2011). The detection was performed on a tripe quadruple tandem mass spectrometer by MRM via electro spray ionization source in positive mode with m/z 428.4 ? 114.4 for peimisine, m/z 237.1 ? 194.2 for carbamazepine (IS). The full scan mass spectrogram of peimisine was depicted in Fig. 2. The separation were preformed on a Phenomenex Luna C18(2) column (2.6 lm, 100 mm 9 2.1 mm ID), The separation was carried out at a flow rate of 0.3 mL min-1 with mobile phase (acetonitrile—10 mmol/L ammonium formate water, 35:65, v/v) and the injection volume was 10 lL. Pharmacokinetic and statistical analysis The concentration versus time profiles were obtained for each individual rat, pharmacokinetic parameter calculation was performed via DAS 2.0 package (Chinese Pharmacological Society) with non-compartmental pharmacokinetic analysis. All the data were expressed as mean ± standard deviation (SD) and statistical analysis were performed by SPSS 16.0 pharmacokinetic parameters and analyte levels in the male and female rats were compared by Independent-Samples T

Fig. 2 Full scan mass spectrogram of peimisine

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L. Chen et al. Table 1 Calibration curves for peimisine in biological samples Biosamples

Linear ranges (ng mL-1)

Calibration curves

Correlation coefficients

Plasma

1–200

Y = 0.0009X ? 0.0051

0.9971

Heart

1–500

Y = 0.0545X ? 0.3055

0.9995

Liver

1–500

Y = 0.0340X ? 0.0604

0.9994

Spleen

1–500

Y = 0.0407X ? 0.2016

0.9995

Lung

1–500

Y = 0.0308X ? 0.3679

0.9982

Kidney

1–500

Y = 0.0482X ? 0.2150

0.9998

Brain Uterus

1–50 1–50

Y = 0.0687X ? 0.3150 Y = 0.0625X ? 0.1275

0.9997 0.9989

Ovary

1–50

Y = 0.0453X ? 0.0890

0.9998

Testis

1–50

Y = 0.0531X ? 0.1172

0.9991

Fat

1–500

Y = 0.0538X ? 0.1270

0.9990

Urine

1–1000

Y = 0.0309X ? 0.3540

0.9992

Feces

1–1000

Y = 0.0427X ? 0.4102

0.9994

Bile

1–1000

Y = 0.0819X ? 0.0372

0.9974

Test and Nonparametric Tests (SPSS 16.0). P \ 0.05 was considered as statistical significance, and P \ 0.01 was deemed to be highly significant difference.

Results Method validation

Fig. 3 Chromatograms of typical tissues, feces, urine and bile, a blank matrix, b blank spiked with peimisine (I) and carbamazepine (II), c vivo samples, respectively. *P \ 0.05, significant difference from female rats; **P \ 0.01, highly significant from female rats

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The LC-MS/MS method developed previously has been validated only for plasma samples. In the present study, the method validation with respect to linearity, lower limit of quantification (LLOQ), extraction recovery, stability, precision and accuracy for tissue, bile, urine and feces samples were further supplemented. Method validation assays were carried out according to the currently accepted bioanalytical method validation guidance (U.S. Food and Drug Administration). Figure 3 illustrated chromatograms of typical tissues, feces, urine and bile after oral administration of peimisine monomer (1.3 mg/kg). Peimisine and IS were eluted at approximately 1.50 and 2.28 min, respectively, no detectable interfering peaks were found. The calibration curves constructed by plotting the peak-area ratios of peimisine to IS versus the nominal concentrations in the standard biological samples using linear regression analysis are listed in Table 1. The calibrations were linear over a certain range in all matrices with correlation coefficient (r2) larger than 0.9971. The LLOQ defined as the lowest concentration at which both precision and accuracy were less than or equal to 20 %, were 1 ng/mL for all the samples. The extraction recoveries from dif-

Pharmacokinetics and excretion of peimisine in rats Table 2 Intra-day and Interday precision and accuracy for peimisine in MRM (multiple reaction monitoring) mode of LC-MS-MS analysis (n = 6)

Sample matrix

Heart

Spiked concentration (ng/mL)

Spleen

Feces

Urine

Bile

Accuracy (mean ± SD, %)

Precision (RSD, %)

92.7 ± 3.1

6.3

91.8 ± 3.5

7.4

94.8 ± 5.9

4.9

90.9 ± 5.8

3.7

2

98.1 ± 2.3

4.5

97.4 ± 9.1

8.6

103.0 ± 6.2

10.1

97.3 ± 6.9

7.2

200

91.7 ± 5.4

9.5

94.4 ± 6.1

3.2

500

96.6 ± 1.9

4.6

95.2 ± 6.0

8.5

2

101.3 ± 5.5

4.8

98.3 ± 5.0

3.9

90.7 ± 3.3

8.0

107.5 ± 2.8

5.0 12.5

500

96.1 ± 2.8

12.1

97.0 ± 6.3

2

98.5 ± 3.7

10.3

93.7 ± 7.1

7.6

200

93.3 ± 5.2

6.6

90.2 ± 5.4

9.4

500 Kidney

Precision (RSD,%)

2

200 Lung

Accuracy (mean ± SD, %)

Inter-day

200 500 Liver

Intra-day

90.1 ± 3.3

7.8

96.7 ± 3.9

6.1

2

100.9 ± 3.8

5.5

90.4 ± 5.7

9.2

200

105.4 ± 6.7

2.4

90.9 ± 5.6

7.5

500

92.8 ± 5.3

6.1

107.4 ± 2.2

8.2 6.6

89.0 ± 8.2

12.2

94.6 ± 3.5

500

2

105.3 ± 4.1

5.4

96.2 ± 5.5

4.7

1,000

109.7 ± 3.9

5.5

90.5 ± 1.9

9.0

2

93.3 ± 2.4

9.2

96.5 ± 3.7

5.3

500

93.4 ± 4.7

2.0

88.9 ± 9.2

1.6

1,000

95.2 ± 5.3

6.4

99.7 ± 5.6

4.7

2

96.0 ± 2.7

3.4

95.4 ± 8.4

3.0

500

91.6 ± 4.5

2.7

92.9 ± 3.5

8.1

1,000

92.9 ± 4.3

9.3

98.8 ± 7.2

5.6

Fig. 4 Mean plasma concentration–time profiles of peimisine after oral administration at a single dose of 0.26 (a), 1.3 (b), 6.5 (c) mg/kg to SD rats (6 males and 6 females)

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L. Chen et al. Table 3 Main pharmacokinetic parameters of peimisine after oral administration at dose of 0.26, 1.3, 6.5 mg/kg to SD rats (n = 6, Mean ± SD) Parameters

ig (Mean ± SD) 0.26 mg/kg Female

1.3 mg/kg Male

6.5 mg/kg

Female

Male

Female

Male b

601.7 ± 212.0*,b

Cmax (ng/mL)

5.6 ± 2.3

17.8 ± 1.7

58.2 ± 14.7

123.6 ± 36.4

181.2 ± 32.4

Tmax (h)

4.0 ± 0.0

4.0 ± 0.0

3.0 ± 1.4

4.0 ± 0.0

4.0 ± 0.0

T1/2 (h) AUC0-t (ng h/mL)

3.2 ± 1.8 26.1 ± 9.7

3.9 ± 1.7 102.3 ± 6.5*

3.1 ± 1.3 478.3 ± 162.0

3.0 ± 0.26 964.4 ± 46.5*

4.8 ± 1.1 1305.7 ± 404.9a

4.5 ± 1.3 5529.5 ± 1628.2*,b

AUC0-? (ng h/mL)

30.0 ± 10.9

117.2 ± 1.2*

480.0 ± 164.4

970.0 ± 49.1*

1389.6 ± 476.2a

5695.8 ± 1372.0*,b

2.8 ± 0.99

1.34 ± 0.07*

5.1 ± 1.7

1.2 ± 0.40*,b

7.9 ± 2.4

5.8 ± 0.22

33.8 ± 7.5

CL/F (L h/kg)

9.6 ± 3.9

2.2 ± 0.02* 12.5 ± 5.7

3.5 ± 1.0

V/F (L/kg)

43.8 ± 27.2

MRT0-t (h)

4.5 ± 0.78

5.0 ± 0.08

9.7 ± 0.28

6.6 ± 0.75

7.8 ± 0.78

8.4 ± 2.8b

MRT0-? (h)

6.1 ± 1.9

6.7 ± 1.1

9.8 ± 0.36

6.7 ± 0.79

9.1 ± 1.6

9.0 ± 3.1

a

P \ 0.05, significant from different doses

b

P \ 0.01, highly significant from different doses

*

P \ 0.05, significant difference from female rats

7.7 ± 2.4

Fig. 5 The linear correlation between dose and Cmax, AUC0-t

ferent matrices were found to be acceptable (91.46– 102.27 %). The intra- and inter-day precision and accuracy for quality control (QC) samples were listed in Table 2. Matrix effect results varied from 89.04 to 96.77 %. The results of stability studies showed that all

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the un-extracted QC samples were stable at room temperature for 6 h, all the processed QC samples in autosampler were stable for 12 h. And after three freeze (-20 °C)–thaw cycles and for 2 weeks at -20 °C, the individual reduction was less than 9.30 %.

Pharmacokinetics and excretion of peimisine in rats

Pharmacokinetics The mean plasma concentration–time profiles after oral administration of peimisine at three doses were depicted in Fig. 4. The corresponding pharmacokinetic parameters generated by fitting plasma concentration profiles to a noncompartmental model are listed in Table 3. The AUC0-t and Cmax values of the three dosages for the specified gender indicated an apparent dose-proportionality as presented in Fig. 5, and there was no significant differences for other parameters including t1\2, Tmax, CL/F and V/F among the three dosages by ANOVA (P [ 0.05). Thus dose linearity of the pharmacokinetics over the examined dosage range was demonstrated. In addition, there were gender differences in the pharmacokinetic parameters of AUC0-t, AUC0-? and CL/F among all the three dosages (P \ 0.05). Tissue distribution Tissue distribution of peimisine was investigated following a single oral administration to rats at 1.3 mg/kg. Peimisine showed substantial disposition in spleen, liver, kidney, lung, and heart, and was detectable in other tissues of rat such as fat, uterus, ovary, testis and brain. The concentrations of peimisine in male tissues were higher than female.

The results of distribution of peimisine at 1, 2, 4, 6 and 8 h were illustrated in Fig. 6. Excretion studies The total cumulative excretion of peimisine over a 24 h period in urine, feces and bile following oral administration of 1.3 mg/kg were illustrated in Fig. 7 and Table 4. In female rats, the cumulative excretion rate of peimisine in urine, feces and bile within 24 h were 13.46, 15.05 and 0.4155 %, while 43.07, 7.49 and 0.6407 % for male rats, respectively. It follows that urine is the primary excrete route in male rats.

Discussion This study investigated the pharmacokinetics, tissue distribution and excretion of peimisine in SD rats. The AUC0-t values of the three dosages (0.26, 1.3 and 6.5 mg/kg) of peimisine indicated an apparent linear doseproportionality with the AUC0-t of approximately 26.1, 478.3, 1305.7 ng h/mL in female rats and 102.3, 964.4, 5529.5 ng h/mL in male rats, respectively. At each time point, the concentrations of peimisine in individual male

Fig. 6 Distribution of peimisine at 1, 2, 4, 6 and 8 h following oral administration of 1.3 mg/kg to SD rats (6 males and 6 females)

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L. Chen et al. Fig. 7 Total cumulative excretion of peimisine in feces, urine and bile following oral administration of 1.3 mg/kg to SD rats (6 males and 6 females)

rat were almost higher than that in female ones. The Cmax values measured for peimisine in male rats were approximately threefold higher than that in female ones. However, the parameters of peimisine showed lower CL/F and V/F in male rats, indicating that the elimination of peimisine was much faster in female rats. The tmax and t1/2 was longer in comparison with the previously reported results (tmax was 0.83 h and t1/2 was 2.13 h), the reason might be the difference of doses or monomer administration in this study. Tissue distribution studies indicated that peimisine was distributed to various of tissues. On the whole, the concentrations of peimisine in male tissues, as well as the plasma, were higher than female animals. In female rats, peimisine showed substantial disposition in spleen, liver, kidney and lung. In male rats, however, the peimisine showed substantial disposition in spleen, kidney, lung and heart. Very low amounts of peimisine were found in brain, indicating that peimisine was difficult to cross the blood–brain barrier. Peimisine was suspected to be teratogenic due to the similar structure with cyclopamine (Zheng et al. 2012; Zhou et al. 2006). In our study, the concentrations of peimisine in uterus, ovary and testis Table 4 Total cumulative excretion of peimisine in feces, urine and bile within 24 h following oral administration of 1.3 mg/kg to SD rats (mean ± SD, n = 6) Cumulative excretion (%)

Female

Male

Urine

13.46 ± 2.93

43.07 ± 15.25

Feces

15.05 ± 4.95

7.49 ± 2.79*

0.4255 ± 0.1611

0.6407 ± 0.1850

Bile

* P \ 0.05, significant difference from female rats

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were relatively less and the eliminations were rapid, indicating that there was no long-term accumulation in the gonads of rats. There were gender differences of peimisine in feces the excretion, but the relative proportions of them in urine did not show the dependency on the gender of rats. Total recoveries of peimisine in urine and feces were about 13.46, 15.05 % in female and 43.07, 7.49 % in male, respectively. In addition, only a small portion of peimisine was excreted in the bile.

Conclusion This is the first report to evaluate the pharmacokinetics, tissue distribution and excretion of peimisine in rats after i.g. administration. Peimisine was slowly distributed and eliminated from rat plasma and showed linear dynamics in a dose range of 0.26–6.5 mg/kg. There were gender differences among the pharmacokinetic parameters of AUC0-t, AUC0-?, and CL/F among the three dosages (P \ 0.05). What’s more, the main distribution tissues of peimisine in rats were spleen, liver, kidney, heart and lung, and a few proportionality of peimisine were excreted in the urine and feces as the unchanged form, the primary excrete route of peimisine is urine in male rats. In this report, we delivered the first thorough studies of the pharmacokinetics, tissue distribution and excretion profiles of peimisine in male and female rats. This work would provide helpful information for the clinical applications or further studies of peimisine.

Pharmacokinetics and excretion of peimisine in rats Acknowledgments Financial supports from the National Natural Science Foundation of China (No. 81060346), Natural Science Foundation of Jiangxi Province (No. 2008GZY0115) and Traditional Chinese Medicine planning of Jiangxi Province (No. 2010A007).

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Pharmacokinetics, tissue distribution and excretion of peimisine in rats assessed by liquid chromatography-tandem mass spectrometry.

Peimisine, the common ingredient of "zhebeimu" groups and "chuanbeimu" groups, is responsible for the expectorant and cough relieving effects. The aim...
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