Pharmacokinetic preformulation study of rH IL-2

Abstract

Pharmacokinetic characteristics of recombinant human interleukin-2-(rH IL-2)were studied in the rat. First, different doses of rH IL-2 ranging from 6400 to 1600000 U/kg were injected intravenously and the effect of dose size on the pharmacokinetics was examined. The result showed that there is no dose dependency in the pharmacokinetics of it in the dose range of 6400-40000 U/kg. It also showed that this drug is hardly distributed to the peripheral tissues and eliminated from the body, since the volume of distribution (Vdss) and total body clearance (CLt) were 45-75 ml/kg and 1-2 ml/min/kg respectively. The Vdss is close to the actual plasma volume, and the CLt is less than glomerular filtration rate (GFR). Therefore it seemed that rH II，2 is distributed only in the plasma pool and hardly filtered in the kidney due to its very large molecular weight. But at the dose of 1600000 U/kg, there was a severe hemolysis throughout the experiment and the pharmacokinetic parameters such as Vdss and CLt were significantly increased compared to the parameters obtained from lower doses. Second, rH IL-2 was administered to the rat via several routes such as hepatic portal vein (pv), intraperitoneal (Ip)，peroral (po) and intranasal (In) routes. The bioavailabilities (BA) of pv, Ip, po and in routes were 96.8, 4.9, 0 and 0.1% respectively. The addition of some nasal absorption enhancer such as taurocholate, taurodeoxycholate, glycocholate and glycodeoxycholated did not increased the BA of intranasaly administered rh IL-2.

The result is contrast to the effect of these bile 期its on the nasal absorption of a-inter-feron. Considering it together with the pharmacokinetic parameters, very large molecular weight of rH IL-2 seemed again to be the cause of very poor membrane permeability.

In order to develop a appropriate delivery system of the rH IL-2, which is rather unstable and has very short biological half life in the body, further studies besides the above studies seems to be necessary.

Bioavailability of intramuscularly injected rH IL-2 is under study by us in order to examine the feasibility of the implant dosage form of rH IL-2.