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Journal of Zhejiang University SCIENCE B 2006 Vol.7 No.3 P.241-244

http://doi.org/10.1631/jzus.2006.B0241


Pharmacokinetic study with N-Ile1-Thr2-63-desulfato-r-hirudin in rabbits by means of bioassay


Author(s):  Han Guo-Zhu, Ren Hong-Can, Lu Yong, Li Ying, Xiao Shu, Ye Hong-Wei, Wang He-Mu

Affiliation(s):  Department of Pharmacology, Dalian Medical Univercity, Dalian 116027, China; more

Corresponding email(s):   hgzhx2236@sina.com

Key Words:  r-hirudin, Pharmacokinetics, Bioassay, Thrombin time, Rabbit


Han Guo-Zhu, Ren Hong-Can, Lu Yong, Li Ying, Xiao Shu, Ye Hong-Wei, Wang He-Mu. Pharmacokinetic study with N-Ile1-Thr2-63-desulfato-r-hirudin in rabbits by means of bioassay[J]. Journal of Zhejiang University Science B, 2006, 7(3): 241-244.

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author="Han Guo-Zhu, Ren Hong-Can, Lu Yong, Li Ying, Xiao Shu, Ye Hong-Wei, Wang He-Mu",
journal="Journal of Zhejiang University Science B",
volume="7",
number="3",
pages="241-244",
year="2006",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.2006.B0241"
}

%0 Journal Article
%T Pharmacokinetic study with N-Ile1-Thr2-63-desulfato-r-hirudin in rabbits by means of bioassay
%A Han Guo-Zhu
%A Ren Hong-Can
%A Lu Yong
%A Li Ying
%A Xiao Shu
%A Ye Hong-Wei
%A Wang He-Mu
%J Journal of Zhejiang University SCIENCE B
%V 7
%N 3
%P 241-244
%@ 1673-1581
%D 2006
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.2006.B0241

TY - JOUR
T1 - Pharmacokinetic study with N-Ile1-Thr2-63-desulfato-r-hirudin in rabbits by means of bioassay
A1 - Han Guo-Zhu
A1 - Ren Hong-Can
A1 - Lu Yong
A1 - Li Ying
A1 - Xiao Shu
A1 - Ye Hong-Wei
A1 - Wang He-Mu
J0 - Journal of Zhejiang University Science B
VL - 7
IS - 3
SP - 241
EP - 244
%@ 1673-1581
Y1 - 2006
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.2006.B0241


Abstract: 
Aim: To study the pharmacokinetic (PK) properties in rabbits treated with N-Ile1-Thr2-63-desulfato-r-hirudin (rH) newly developed in China by means of bioassay in order to provide preclinical experiment basis for its development as a novel anticoagulant agent. Methods: rH plasma concentration was determined using bioassay based on ex vivo antithrombin activity of rH. Normal rabbits received iv rH 4.0, 2.0 and 1.0 mg/kg or sc rH 2.0 mg/kg, respectively. The rabbits with acute severe renal failure were given iv rH 2.0 mg/kg. Results: The bioassay described in this paper met requirements for study of PK in rabbits. The major PK parameters after iv dosing were as follows: t1/2β 58.4~59 min. Vd 0.09~0.12 L/kg, CL 0.0035~0.0040 L/(kg∙min); AUC were proportional to the doses, t1/2 and CL did not change significantly with the doses. The sc bioavailability reached 94%. The rabbits suffering from acute severe renal failure presented 11-fold longer t1/2β and 13-fold greater AUC than normal healthy rabbits. Conclusion: rH exhibited rapid elimination, distribution was only limited to extracellular space and good absorption from sc site. The excretion of rH by kidneys played a very important role in the elimination of rH. The PK of rH could be described by the two- and one-compartment model after iv and sc dosing, respectively, and followed linear kinetics.

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Reference

[1] Han, G.Z., 2003. Review of pharmacokinetics of hirudin, a directly-acting thrombin inhibitor. Asian Journal of Drug Metabolism and Pharmacokinetics, 3(1):65-70.

[2] Jiang, S.Y., Li, G.X., Han, G.Z., 2003. Pharmacokinetic study with r-hirudin in rats. Asian Journal of Drug Metabolism and Pharmacokinetics, 3(2):129-133.

[3] Lu, L., Wang, C.Y., Han, G.Z., Li, X.Y., Tian, Y., 2002a. Experimental study on antithrombotic and anti-DIC effects of rH in animals. Journal of Chinese Pharmaceutical Sciences, 37(9):707-708 (in Chinese).

[4] Lu, L., Li, X.Y., Han, G.Z., Wang, H.M., 2002b. Experimental studies on in vivo anticoagulant activity of recombinant hirudin in rabbits. Chinese Traditional Herbal Drugs, 33(6):520-523 (in Chinese).

[5] Markwardt, F., 1994. The development of hirudin as an antithrombotic drug. Thrombosis Research, 74(1):1-23.

[6] Ren, H.C., Han, G.Z., Lu, Y., Li, Y., Ye, H.W., 2005. A bioassay for the determination of recombinant hirudin in the plasma of rabbits. Asian Journal of Drug Metabolism and Pharmacokinetics, 5(3):223-229.

[7] Tang, Z.M., Liu, X.W., Chai, B.X., 1996. Methods and experimental design of pharmacokinetic studies on protein and polypeptide drugs. Chinese Journal of Pharmacology and Toxicology, 10(3):161-163.

[8] Zhou, Q., Ren, K.H., Han, G.Z., Li, W.P., 2005. Experimental study on the inhibitory effects of recombinant hirudin on middle cerebral artery thrombosis of rats. Chinese Traditional Herbal Drugs, 36(1):84-86 (in Chinese).

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