향류마치스 효과를 갖는 새로운 히스톤 Hl 단백질 (p961)의 횐쥐와 토끼에 대한 약물동태

Pharmacokinetics of a New Histone Hl Protein (p961), an Arthritis-suppressing Agent, in Rats and Rabbits

A purified histone Hl protein, p961, which plays a role in mediating the condensation of DNA into chromatin, was recently proved as an arthritis-suppressing agent in the mouse CIA model. The pearmacokinetics of p961 was carried out in rats and rabbits. The rat's blood, bile and urine samples were semially collected from the femoral vein, common bile duct, and bladder respective1y; after bolus I.v. injection at low (10 mghg) and high (30 mg/mg) doses. The rabbit's blood samples were also collected from the marginal ear vein after bolus I.Y. injection at a dose 10 mg/kg. P961 and its major metabolite in the physiological samples were analyzed by reverse-phase HPLC using a Vydac C4 protein column and a multistep water-acetonitrile gradient containing 0.24% trifluoroacetic acid. The major pharmacokinetic parameters (AUC, Cmax, MRT t1/2, Vss and Cl) were estimated from the time course of plasma p961 and metabolite concentrations using WinNonlin. A two- compartment model was chosen for p961 as the most appropriate pharmacokinetic model. After I.v, injection of p961 at doses of 10 mghg and 30 mg/kg, more than 80% of p961 was removed rapidly from the plasma within 15 min. The plasma half-life of p961 in rats and rabbits was found not to exceed 12 min. p961 (22448.9 mot wt) was rapidly cleaved to 21612 mol wt fragment and the breakdown product appeared rapidly in the circulation with no lag phase. P961 and metabolite were not detected in rat urine and bile.