全 文 ：·药剂·
Dynamic Studies on the Distribution and Excretion of　 3H-Kopsinine 1 in Rats
Wang Liqiang ( Wang LQ) , Li Liangqiao ( LiLQ) , Miao Licheng ( Miao LC) , Wu Chaolun( Wu CL) (No. 211
Hospital of P LA , Harbin 150080)
ABSTRACT　 OBJECTIVE: T o study the tissue distribution and exc retion of　 3H-Kopsinine 1 in ra ts. METHODS: 　 H-
Kopsinine 1 w ere administrated to 7 g roups o f 6 ra ts or ally o r intrav enously , then blo od, o rg an, urine, feces and bile w ere
collected to prepare sample so lutions. After 12 h ours, the radio activity was measured by Liquid Scintilla tion Counter.
RESUTS: The r adioactiv ity time curv e can be desc ribed by a two compa rtment model. The T1 /2αand th e T1 /2β is 12 minutes
and 28. 1 hour s respectiv ely. After or al administra tion th e radio activity in liv er a t 1 hour wa s 277. 5± 17. 8ng /g and tha t in
Kidney w as 182. 4± 12. 0ng /g . The majo rity ( 66% ) o f radio activity wa s recovered fr om urine in 24 hours and 14% of
radio activity wa s fr om bile in 48 hour s. CONCLUSION: Results suggest tha t liv er is the main effectiv e o rg an o f Kopsinine 1,
and a lso , Kopsinine 1 has a little po ssibility fo r enterohepatic circula tion.
KEY WORDS　 Kopsinine 1, distribution, , ex cre tion, pharmacokinetics
蕊木宁在大鼠体内分布与排泄的动态研究
王立强　李良桥　苗立成　巫朝伦 (哈尔滨 150080解放军 211医院 )
摘要　目的: 研究云南蕊木中有效成分蕊木宁在大鼠体内的组织分布与排泄。方法:将蕊木宁用放射性元素 3H标记 ,分别以静
注和口服方式给予受试大鼠 ,收集血液、脏器、尿液、胆汁等 ,用液体闪烁记数仪测量其放射活性。 结果:血中的放射活性呈二
相衰减 , t1 /2α为 12min, t1 /2β 28. 1h。口服给药 1h后 ,肝脏中的放射物浓度为 277. 5± 17. 8ng /g ,肾脏为 182. 4± 12. 0ng /g;并
且 , 48h内 ,大部分放射活性 ( 66% )由尿液排泄 ,小部分 ( 14% )由胆汁排泄。 结论: 肝脏可能是蕊木宁的主要靶器官 ,且蕊木宁
自身产生肝肠循环的可能性较小。
关键词　蕊木宁 ;分布 ;排泄 ;药代动力学
　　 One of the traditional Chinese m edicines, Yunnan-Xin-
Mu ( YXM ) is prepar ed from roots and leaves of Kopsia
o fficinalis T siang e t P. T. Li in China. Kopsinine 1 is known
to be an activ e compound o f YXM , usually used fo r the
tr eatment o f bone ach e and hepa tic disease. Although many
pha rmaco lo gical studies o f Kopsinine 1 have been done,
pha rmacokinetic study has no t been repo rted [1] . In this
pape r, pha rmacokinetic studies of Kopsinine 1 w ere
examined with radio activ e compound. The rela tionship
betw een pha rmaco log ical effec ts and pharmacokinetics o f
Kopsinine 1 w as discussed.
MATERIAL AND METHOD
Drug: 3H-Kopsinine 1 w as prepared by China institute
o f Atom Energy ( Beijing ) . Its specific radioactivity is 153. 9
Ci /mol and the radio purity is mo re than 98% . The
unlabeled Kopsinine I was isolated fr om YXM in our
labo ra tor y and identified. All o ther chemicals with the
high est g r ade w ere from commercial source.
Animals: Ma le wistar /ST rats, 6 w eeks old ( 150-200g
body weight ) , we re purchased fr om Be thune Medical
Univ ersity ( China ) . The anima ls w ere bred in a breeding
r oom with temperatur e of 24± 1℃ , humidity o f 50± 5% and
12 hours da rk-light cycle fo r 3 days. They w ere giv en tap
w ater and no rmal tbods ad libitun. Th e r ats in o ral
administr ation g r oup were fasted about 24 h befo re
expe riment.
Apparatus: Radioactiv ity Measurem ent w as ca rried out
by Parka rt Model 4430 Liquid Scintillation Counter ( Parka rt
Instr ument Co. Inc. U. S. A)
Drug preparatlon: A) Fo r i. v . injection: 3H-Kopsinine 1
w as disso lv ed in me thano l to giv e the so lution of 1 mg /m L.
3. 5 mL of the so lution was added to 96. 5m L o f distilled
w ater unde r stirring . This so lution ( 100ml ) wa s nam ed
prepara tion A. Radioactiv ity of pr epar ation A w as adjusted
to 26. 08 μCi /m L , and then the dose ( 350 p g /kg ) of
prepara tion A was calcula ted to 260. 8μCi /kg . B) For o ral
·32· Ch in JM AP, 2002 Feb ruary, Vol. 19 No. 1　　　　　　　　　　　　　　　中国现代应用药学杂志 2002年 2月第 19卷第 1期
DOI : 10. 13748 /j . cnki . i ssn1007 -7693. 2002. 01. 014
administr ation: 0. 8 m L o f　 3 H-Kopsinine 1 methanol
solution w as added to 24. 2 mL o f distilled wa ter unde r
stirring . This so lution ( 25 mL ) wa s named prepara tion B.
Radio activity o f prepara tion B was adjusted to 0. 78 μCi /
m L, and then th e do se ( 640 μg /kg ) of prepar ation A w as
calcula ted to 7. 8μCi /kg.
Blood sample preparation: Aft er i. v . injection of　 3 H-
Kopsinine 1, blood w as co llected fr om orbital ma rgin vein o f
ra t in designed time period. 0. 1 m L of blood w as poured
into the mix tur e of fo rmic acid solution ( 88% ) -hydro gen
pero xide ( 30% ) -noctano l( 4∶ 3∶ 0. 5) , th en th e mix ture w as
incuba ted in w ater ba th a t 80℃ fo r 45 min. After co oling to
r oom temperatur e, the r adioactiv ity o f the mix ture w as
measured.
Preparation of organ tissue sample: After i. v . injection
o f　 3H-Kopsinine 1, the o rg ans o f ra t we re collected in
designed time period. The o rgans w ere wa shed with iso lonie
solution, and was cleaned with Kimtowel ( Kimbery-Cla rk
Co. Inc, Japan ) befo re homogenization. 50 mg o f each
homogenate w as put into the mix ture of fo rmic acid so lution
( 88% ) -hydrogen per ox ide ( 30% ) -noctanol ( 4∶ 3∶ 0. 5) .
Then it was t reated in the same way as mentioned above.
Ur ine sample preparation: After ora l administra tion o f
prepara tion B, urine wa s co llected about 0. 5m L in designed
time pe riod. Then th e co llected urine was diluted to 20 m L
with w ater.
Bile sample preparation: A po ly ethylene tube ( fr ,
No3, Hibiki ) w as inser ted into the r at bile duct unde r
amoba rbital anesthesia. After or al administra tion o f
prepara tion B to the opera ted ra t, bile w as co llected about 0.
5mL a t designed interv al. Then it w as trea ted with th e same
method mentioned in blood sample[2 ].
Radioactivity detection; 3 H-Kopsinine 1 w ere
administr ated to 7 g roups of 6 ra ts by ora lly o r
int rav enously. Blood, urine, feces and bile wer e collec ted
prior to o rg an in designed time period ( befo r e the o rgans
w ere collec ted, the animals must be put to death ) . Then
they w ere tr eated to g et sample so lutions by the method
mentioned above. 0. 1 m L of sample solution w as added to
the mix tur e o f 2-ethoxye thano l-PPO xylene so lution( 4∶ 6) .
After 12h , the radioac tiv ity was measur ed by Liquid
Scintilla tion Counter ( Parka rt M odel 4430) .
Data analysis: Th e radioac tiv ity-time curv e was plot ted
semilog arithmically . The ha lf-life ( T1 /2) wa s ca lcula ted
fr om the linea r region by linear r eg ression ana ly sis. The
ar ea under th e plasma concentration-time curv e ( AUC) was
calculated by the t rapezoidal method fr om a g raph fo r up to
48 h [3] .
RESULT
Rodioact ivity-time course in blood: Blo od was co llected
at 3, 5, 20 min and 1, 8, 24 and 4g h after i. v. injection o f3 H-
Kopsinine 1 and their radioac tiv ities w ere detected ( Table
1) . The radioactiv ity in blood is show n as 320. 3± 18. 5ng /
m L after administra tion and 90. 0± 4. 4ng /m L 60 min later.
The radioa ctivity time curv e can be described by a tw o
compar tment model. The T1 /2α and the T1 /2 β is 0. 20h,
28. 1h respectiv ely ( Fig. 1, Table2) .
Distribution of radioactivity in organ tissue: Af ter i. v.
injec tion, o rgan w ere co llected fr om 3 min to 48 h. The
highest lev el of radioac tiv ity was found in kidney and liv er.
The lev el of radioactiv ities w ere mode rated in blo od, lung
and hea rt, a nd those in testis and fat w ere the low est( Table
1 ) . The elimina tion r ate of r adioactiv ity in liv er w as much
slow er than that o f kidney . As the radio activity in liv er a t 1
hour w as 277. 5± 17. 8 ng /g and tha t in kidney is 182. 4±
12. 0ng /g , it w as considered that the drug still concentra ted
in liv er.
Table 1　 Distribution o f Radioactiv ity af ter O rai Administration of　 3H-Kopsinine 1
Tis sue
Concent rat ion( ng /g or ml of　 3H-Kopsinie 1) a )
3min 5min 20min 1h 8h 24h 48h
Blood 320. 3± 18. 5 260. 1± 34. 1 175. 2± 3. 6 90. 0± 4. 4 75. 1± 3. 8 50. 4± 8. 0 26. 8± 2. 9
Liver 389. 4± 147. 6 944. 5± 54. 8 438. 5± 30. 5 277. 5± 17. 8 136. 0± 9. 1 104. 1± 21. 4 71. 5± 7. 6
Spleen 107. 7± 14. 1 142. 5± 7. 6 111. 0± 8. 2 89. 2± 15. 2 68. 9± 6. 5 49. 7± 5. 8 38. 1± 5. 4
Lung 308. 7± 61. 3 397. 5± 45. 7 165. 8± 9. 8 127. 7± 10. 5 92. 5± 6. 9 56. 9± 12. 0 28. 7± 2. 2
Kidney 1391. 4± 214. 0 2154. 9± 94. 3 640. 2± 60. 2 182. 4± 12. 0 131. 7± 16. 7 56. 9± 2. 5 35. 2± 2. 5
Tes ti s 41. 7± 6. 5 79. 1± 5. 1 68. 2± 4. 4 58. 0± 7. 6 47. 2± 4. 7 40. 6± 2. 2 31. 6± 5. 4
Far 31. 9± 8. 7 72. 2± 2. 2 66. 0± 2. 5 46. 1± 4. 7 28. 3± 7. 3 19. 6± 3. 6 14. 1± 2. 5
Brain 51. 1± 7. 6 80. 5± 6. 5 58. 0± 8. 7 49. 7± 8. 3 37. 0± 2. 9 29. 0± 2. 9 22. 5± 2. 2
Sub. Gland 119. 3± 24. 7 164. 3± 18. 9 108. 8± 8. 7 76. 9± 5. 8 44. 6± 2. 2 30. 5± 2. 5 20. 7± 4. 7
Ad r. gtand 98. 3± 16. 7 146. 9± 32. 3 124. 8± 10. 9 87. 4± 18. 9 64. 6± 10. 9 45. 0± 5. 1 25. 4± 5. 8
Th ymus 81. 2± 21. 0 156. 7± 21. 8 96. 8± 7. 6 62. 4± 16. 7 41. 0± 2. 5 30. 1± 3. 3 18. 5± 2. 9
a) The Data are express ed as the mean± SD of six rat s.
·33·中国现代应用药学杂志 2002年 2月第 19卷第 1期　　　　　　　　　　　　　　　 Chin JM AP, 2002 Feb ruary,Vol. 19 No. 1
Table 2　 Pha rmacokine tic Parameters of　 3H-Kopsinine 1 in
Blo od
Parameter V alue
T1 /2α( h) 0. 20
T1 /2β ( h) 28. 09
AU C(mg. h /L) 2. 67
V d( L /kg) 3. 86
a) The m ean value f rom 7 groups of 6 rats.
Excretion in urine and bile: 3 H-Kopsinine 1 w as
excreted fr om urine and bile when administra ted or ally. The
majority o f radioa ctivity ( 66% ) was excreted in urine in 24
hour s and sma ll amount o f it( 14% ) was exc reted in bile in
48h. Th e general r esult w as shown in Fig. 2 and Fig. 3.
Fig. 1　 Time Cour se o f Radioac tiv ity in Liv er and Kidney
after Intrav enous Administra tion o f　 3 H-Kopsinine 1
Fig. 2　 Time Course o f Radio activity in U rine after O ral
Administra tion o f 0. 35mg /kg o f　 3 H Kospinine 1
Fig. 3　 T ime Course o f Radioactiv ity in Bile af ter O ral
Administra tion o f　 3 H-Kopsinine 1( n= 6)
DISCUSSION
The radioac tivity in blo od after int ravenous injection of
　 3 H-Kopsinine 1 distributed to o rg an tissue ve ry soon. The
blo od lev el of radioactiv ity decreased in tw o phases, namely
the distribution pha se and the elimination pha se , with the
T1 /2αof 0. 20h and T1 /2β o f 28. 1 h. The pharmacokinctic
prope rties a re differ ent from the parameter s obtained by
HPLC method. By using radio activ e Kopsinie 1, the o riginal
fo rm as w ell as its metabo lites can be detected. But chemical
method determined only the original form of Kopsinine 1.
Since both Kopsinine 1 and its metabolites have the
pha rmaco lo gica l activity[4 ]. So the sensitiv ity of HPLC-UV
method is much lowe r than that of the radio activity.
The refo re, r esults from the HPLC method missed the
elimination pha se. Th e T1 /2 ( 11 min ) of Kopsinine 1
obtained by HPLC was almost th e same a s T1 /2 α by
radioactivit y. The pha rmacokine tic pa ramete rs by
radioactivit y can explain the maintenance of cho ler etic effect
much be tter than tha t by HPLC.
After intrav enous injection of　 3H-Kopsinine 1 the lev el
o f radio activity w as the highest in kidney and liv er. Kidney
and liv er a re the main o rg an fo r ex creting and me tabo lism.
The radio activity in liv er wa s the highest a t 1 hour af ter
administr ation, and the decr easing r ate wa s the slow est.
This phenomenon suggested tha t liv er is the main a ffinitiv e
o rg an o f the crude drug , which is confo rmed to tr aditional
Chinese m eaicine theor y. Finnally it w as exc reted in urine
and bile. The majority o f radioa ctivity w as excr eted in
urine. Comparing to the excr etion in urine , th e r adioactiv ity
ex creted in bile w as a t a v e ry low level. The reason might be
own to the mo lecule w eigh t ( 338) o f Kopsinine 1, because
the compound below 400 mo lecule w eight is difficult to
·34· Ch in JM AP, 2002 Feb ruary, Vol. 19 No. 1　　　　　　　　　　　　　　　中国现代应用药学杂志 2002年 2月第 19卷第 1期
excrete from bile[5] . Our result confirms to the above
theo ry. And the results also suggest tha t Kopinine 1 ha s a
little possibility for enteroh epa tic circula tion.
REFERENCE
1 Zh eng J J, Li F, Liu M , et al. Indole alk aloid s f rom Kopsia
of f icinali s. Acta Chim Sin( Engli shed) , 1989, 2: 168.
2 Zhou Y L, Wei XP, Ding YB, et al. A s tudy on th e alkaloids of
Kopsia of ficinalis. Acta Ch im Sin, 1989, 42: 1315.
3 黄婉芸 ,刘耕陶 .蕊木宁对小鼠肝微粒混合功能氧化酶的诱导
作用 .中国药理学报 , 1990, 11: 264.
4 中国医学科学院药物研究的编著 .中草药现代研究 .北京医科
大学中国协和医科大学联合出版社 , 1995. 188.
5 Yoshinobu K. Planta Med, 1993, 59( 2): 46.
收稿日期: 2000- 09- 05
695例茶碱血药浓度监测分析
王衍洪　王　成　黄永英 1 (东莞 523013东莞东华医院 ; 1广州 510150广州市第二人民医院 )
摘要　目的: 了解影响茶碱血药浓度的因素以指导临床用药。方法:本文对接受茶碱维持量疗法的 695例患者的茶碱血药浓度
监测结果进行了回顾性分析。 结果: 35. 1%的病例茶碱血药浓度在有效血药浓度范围内 ( 10～ 20μg /m l) , 35. 8%的病例茶碱血
药浓度低于 10μg /ml, 29. 1%的病例茶碱血药浓度高于 20μg /ml;环丙沙星、氟罗沙星 、沙丁胺醇提高茶碱血药浓度 ;特布他
林、利福平、速尿降低茶碱血药浓度 ;合并肝功能异常、肺心病患者茶碱血药浓度偏高 ;嗜烟患者茶碱血药浓度偏低。 结论:茶
碱血药浓度个体差异大 ,药物因素、疾病因素、嗜好等影响茶碱血药浓度 ,茶碱血药浓度监测对提高其使用的安全性和有效性
具有重要的意义。
关键词　茶碱 ;血药浓度 ;环丙沙星 ;特布他林
Analysis of serum concentration of the ophyll ine in 695 patients
Wang Yanhong ( Wang YH) , W ang Cheng ( Wang C) , Huang YongYin ( Huang YY) (Donghua Hospital ,
Dongguan 523013)
ABSTRACT　 OBJECTIVE: To realize the facto rs of affecting th e serum concentr ation o f theoph ylline. METHOD: The data
o f 695 patients who whose the se rum concentr ation o f theophy lline we re dete rmined analy zed. RESULTS: 35. 1% of the ca ses
had the effective serum concentr ation of theophylline ( 10～ 20μg /ml) , 35. 8% cases had relativ ely low er concent ration, and
29. 1% cases had relativ ely highe r. Cipro flo x acin, fle ro racin and salbutamol increase th e serum concentra tion of theophylline.
Te rbutaline, rifampicin, and lasix decr ea se the serum concentra tion o f th eoph ylline. The pa tients with abno rma l liv er
func tion o r pneumo-ca rdiopathy have the prone to make the serum concent ration o f theophy lline on the high side, wher eas the
patients being addic ted to smoking have the prone to make the serum concentration of theophy lline on the low side.
CONCLUSION: There is g rea t individual diffe rence in th e serum concent ration o f theophy lline, facto rs o f combining drugs
and o ther diseases and hobbies will affect the se rum concentr ation o f theophylline. The study indicat ed that it is impo r tant to
improve the sa fety and effec tiv eness of theophy lline to monito r the serum concent ration.
KEY WORDS　 Theophylline, Serum concentr ation Ciproflox acin, sa lbutamo l
　　茶碱是治疗支气管哮喘常用药物 ,其血药浓度与不良反
应有密切关系。 药物的相互作用、患者的个体差异等多种因
素影响茶碱血药浓度 ,使茶碱血药浓度升高或降低 ,可能会
产生毒副反应或者未能达到预期的治疗效果。本文对 695例
患者的茶碱血药浓度监测结果进行了回顾性分析 ,探讨各种
因素对茶碱血药浓度的影响 ,为临床安全、合理用药提供参
考。
1　材料和方法
1. 1　病例
喘息型慢性支气管炎、支气管哮喘患者、慢性阻塞性肺
病 ( CO PD) 695例 ,为内科住院患者和出院后随访患者。其中
男性 433例 ,年龄 55～ 70岁 ;女性 262例 ,年龄 50～ 74岁。各
患者均接受茶碱维持量疗法 ,使用茶碱缓释片优喘平 (美国
先灵葆雅药厂 ) , 0. 25q12h ( 8∶ 00am和 8∶ 00pm服用 )。分析
组为合用环丙沙星、氟罗沙星、沙丁胺醇等和合并有肝功能
不全、肺心病以及嗜烟的病例 ,年龄 50～ 74岁 ;对照组为无
影响茶碱血药浓度因素存在的病例 ,共 151例 ,年龄 56～ 73
岁。
·35·中国现代应用药学杂志 2002年 2月第 19卷第 1期　　　　　　　　　　　　　　　 Chin JM AP, 2002 Feb ruary,Vol. 19 No. 1