Study on pharmacokinetics for TDDS of oxymatrine
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《中华医药杂志》英文版
[Abstract] Objective To investigate the oxymatrine pharmacokinetics for TDDS in vivo,and so proved whether it is changed into matrine from oxymatrine after TDD.Methods To take the pharmacokinetics parameters by determining the mean concentration in blood of rats.HPLC was used in the analysis.Results T(peak) was 8.88h;C(max) was 1.198μg/ml;Auc was 36.217(μg· ml)/h.The pharmacokinetics equation was C=-4.44928·e-0.209479t+3.65729·e-0.11999t.+0.79199·e-0.029358t.Conclusions A kind of 2-compartment model with 1st order absorption is proved.And the oxymatrine is not changed into matrine after TDD.
[Key words] oxymatrine;biotransformation;pharmacokinetics
INTRODUCTION Oxymatrine is one of the effective components of Sophora Flavecens Ait which is the traditional Chinese medicine.The alkaloids as matrine type have a lot of pharmacological effects.It's effect of antiarrhythmia is very obvious[1,2].The oxymatrine will be changed into matrine by biotransformation after oral application according to documents[3],but there are not reports whether it may be changed after paste TDDS.And so the study has been done deeply which is reports as follows.
MATERIALS AND METHODS
Materials
Waters 600-2487HPLC instrument,computer,analytical balance,Super-thermostatic water bath,oxymatrine and it's TDDS;methanol(CG),acetonitrile(CG)and other agents.The experimental animal was Wistar rats.
Methods
Analytical Method
HPLC Conditions The stationary phase was Nucleosil NH2 column.The mobile phase is acetonitrile-ethanol-pH 1.8 phosphoric acid (80∶10∶8).The temperature of column is 18℃.The detective wave was 220 nm.The flow rate is 1.2 ml/min.
Preparation of standard curve The standard solutionwas to use the blank blood serum to dissolve the oxymatrine.And then the standard curve was prepared through detecting by above HPLC conditions.The data were included in Table 1.
Table 1 The data of standard curve
The data were regressed linearly and the regression equation was taken as below.
C=1.1219×10-3+4.158×10-6A(r=0.9993)
This shows that the coherency is obvious and there is better linear correlation between 0.00576~0.0288μg.
Experimental method First 12 healthy rats were chosen which weighted 200~250g.Twenty-four hours before experiment the hair above the rats left breasts were removed with 10% sulfide and cleaning.Twelve hours before paste the oxymatrine TDDS the rats were fasted and at 1 hour after taking medicine the food was given.
In the experiment,the TDDS of oxymatrine was glued to the moulted place firmly and firmed with adhesive plaster.After taking medicine,the blood was taken
1.Heilongjiang University of Traditional Chinese Medicine,Harbin 150040,Heilongjiang Province,China
2.Zhejiang Higher School of Medicine,Hangzhou 310053,Zhejiang Province,China
Correspondence to WANG Jian-ming,Heilongjiang University of Traditional Chinese Medicine,Harbin 150040,Heilongjiang Province,China
Tel:+86-451-82196262 Fax:+86-451-82196262 E-mail:wangjianming@hljucm.net
from the rat eye for 0.5 ml by the capillary tube with anticoagulant,and then dissolved with 5 ml methanol and mixed with mixing oscillator for 1 min.The extractive solution was centrifugalized by 3000 r/min for 10 min and the above solution was taken out and evaporaized by 70℃ water bath.The residue was dissolved into the 10 ml measuring flask with methanol to the graduation and taking 20 μl to determine as above HPLC conditions.The contents of oxymatrine were calculated by extra-standardizing and the pharmacokinetics parameters were computed through inputting the data with computer program.
RESULTS
The HPLC map showed that there was oxymatrine peak (the retention time about 11.8 min) obviously and was not the matrine peak (the retention time about 8.8 min) (Figure 1).
Figure 1 HPLC of blood sample(oxymatrine)
The result showed that it was a kind of 2-compartment model with 1st order absorption.The data of blood concentration and the pharmacokinetics parameters were included in Table 2 and Table 3 respectively.
Table 2 The data of average blood concentration of oxymatrine (x±s,μg/ml)
Table 3 Pharmaceutics parameters
The equation was fitted according to the 2-compartment model,below.
C=N·e-kat+ L·e-αt+M·e-βt
=-4.44928·e-0.209479t+3.65729·e-0.119990t+0.79199·e-0.029358t
DISCUSSION
After oxymatrine was used by TDDS the HPLC behavior of the drug in blood showed that there was not biotransformation and maintained prototype.The absorption of oxymatrine was slower than matrine,it's t peak was 8.88 h and c max was 1.198 μg/ml,but to be 7.76 h and 9.998 μg/ml to matrine respectively.This condition was different to the report of document[3] in which oxymatrine must be changed into matrine after oral application.
It was also different from injecting application because there is a absorption process by TDDS and the characteristic of continuing administration.
Funding：Supported by the Heilongjiang Committee of Science and Technology(NO.GB02C110),China
REFERENCES
1. 李丹,王平全,张楠森,等.苦参碱类生物碱的研究进展及临床应用.中草药，1996，27(5)：308-311.
2. 张宝恒,孔祥军,蔡育立,等.氧化苦参碱的抗心律失常作用.北京大学学报(医学报)，1988，20(6)：419-421.
3. 谢明智,周文正,张瑛,等.氧化苦参碱的代谢.药学学报，1981，16(7)：481-486.
(Editor Emilia)(WANG Jian-ming1，WANG He-p)
[Key words] oxymatrine;biotransformation;pharmacokinetics
INTRODUCTION Oxymatrine is one of the effective components of Sophora Flavecens Ait which is the traditional Chinese medicine.The alkaloids as matrine type have a lot of pharmacological effects.It's effect of antiarrhythmia is very obvious[1,2].The oxymatrine will be changed into matrine by biotransformation after oral application according to documents[3],but there are not reports whether it may be changed after paste TDDS.And so the study has been done deeply which is reports as follows.
MATERIALS AND METHODS
Materials
Waters 600-2487HPLC instrument,computer,analytical balance,Super-thermostatic water bath,oxymatrine and it's TDDS;methanol(CG),acetonitrile(CG)and other agents.The experimental animal was Wistar rats.
Methods
Analytical Method
HPLC Conditions The stationary phase was Nucleosil NH2 column.The mobile phase is acetonitrile-ethanol-pH 1.8 phosphoric acid (80∶10∶8).The temperature of column is 18℃.The detective wave was 220 nm.The flow rate is 1.2 ml/min.
Preparation of standard curve The standard solutionwas to use the blank blood serum to dissolve the oxymatrine.And then the standard curve was prepared through detecting by above HPLC conditions.The data were included in Table 1.
Table 1 The data of standard curve
The data were regressed linearly and the regression equation was taken as below.
C=1.1219×10-3+4.158×10-6A(r=0.9993)
This shows that the coherency is obvious and there is better linear correlation between 0.00576~0.0288μg.
Experimental method First 12 healthy rats were chosen which weighted 200~250g.Twenty-four hours before experiment the hair above the rats left breasts were removed with 10% sulfide and cleaning.Twelve hours before paste the oxymatrine TDDS the rats were fasted and at 1 hour after taking medicine the food was given.
In the experiment,the TDDS of oxymatrine was glued to the moulted place firmly and firmed with adhesive plaster.After taking medicine,the blood was taken
1.Heilongjiang University of Traditional Chinese Medicine,Harbin 150040,Heilongjiang Province,China
2.Zhejiang Higher School of Medicine,Hangzhou 310053,Zhejiang Province,China
Correspondence to WANG Jian-ming,Heilongjiang University of Traditional Chinese Medicine,Harbin 150040,Heilongjiang Province,China
Tel:+86-451-82196262 Fax:+86-451-82196262 E-mail:wangjianming@hljucm.net
from the rat eye for 0.5 ml by the capillary tube with anticoagulant,and then dissolved with 5 ml methanol and mixed with mixing oscillator for 1 min.The extractive solution was centrifugalized by 3000 r/min for 10 min and the above solution was taken out and evaporaized by 70℃ water bath.The residue was dissolved into the 10 ml measuring flask with methanol to the graduation and taking 20 μl to determine as above HPLC conditions.The contents of oxymatrine were calculated by extra-standardizing and the pharmacokinetics parameters were computed through inputting the data with computer program.
RESULTS
The HPLC map showed that there was oxymatrine peak (the retention time about 11.8 min) obviously and was not the matrine peak (the retention time about 8.8 min) (Figure 1).
Figure 1 HPLC of blood sample(oxymatrine)
The result showed that it was a kind of 2-compartment model with 1st order absorption.The data of blood concentration and the pharmacokinetics parameters were included in Table 2 and Table 3 respectively.
Table 2 The data of average blood concentration of oxymatrine (x±s,μg/ml)
Table 3 Pharmaceutics parameters
The equation was fitted according to the 2-compartment model,below.
C=N·e-kat+ L·e-αt+M·e-βt
=-4.44928·e-0.209479t+3.65729·e-0.119990t+0.79199·e-0.029358t
DISCUSSION
After oxymatrine was used by TDDS the HPLC behavior of the drug in blood showed that there was not biotransformation and maintained prototype.The absorption of oxymatrine was slower than matrine,it's t peak was 8.88 h and c max was 1.198 μg/ml,but to be 7.76 h and 9.998 μg/ml to matrine respectively.This condition was different to the report of document[3] in which oxymatrine must be changed into matrine after oral application.
It was also different from injecting application because there is a absorption process by TDDS and the characteristic of continuing administration.
Funding：Supported by the Heilongjiang Committee of Science and Technology(NO.GB02C110),China
REFERENCES
1. 李丹,王平全,张楠森,等.苦参碱类生物碱的研究进展及临床应用.中草药，1996，27(5)：308-311.
2. 张宝恒,孔祥军,蔡育立,等.氧化苦参碱的抗心律失常作用.北京大学学报(医学报)，1988，20(6)：419-421.
3. 谢明智,周文正,张瑛,等.氧化苦参碱的代谢.药学学报，1981，16(7)：481-486.
(Editor Emilia)(WANG Jian-ming1，WANG He-p)