Pharmacokinetic study with N-Ile1-Thr2-63-desulfato-r-hirudin in rabbits by means of bioassay.
OBJECTIVE
To study the pharmacokinetic (PK) properties in rabbits treated with N-Ile(1)-Thr(2)-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: t(1/2beta) 58.4-59 min. V(d) 0.09-0.12 L/kg, CL 0.0035-0.0040 L/(kg.min); AUC were proportional to the doses, t(1/2) 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 t(1/2beta) and 13-fold greater AUC than normal healthy rabbits.


CONCLUSIONS
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.
Han
Guo-zhu
GZ
Department of Pharmacology, Dalian Medical Univercity, Dalian 116027, China. hgzhx2236@sina.com
Ren
Hong-can
HC
Lu
Yong
Y
Li
Ying
Y
Xiao
Shu
S
Ye
Hong-wei
HW
Wang
He-mu
HM
D000465:Algorithms; D000818:Animals; D001681:Biological Assay / Q000379:methods*; D003198:Computer Simulation; D006629:Hirudins / Q000097:blood* / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011817:Rabbits; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013918:Thrombin Time / Q000379:methods*
D006629:Hirudins; C510277:recombinant hirudin, Ile(1)-Thr(2)-63-desulfato-