The pharmacokinetic pattern of glycosylated human recombinant lymphotoxin (LT) in rats after intravenous administration.
We have examined the pharmacokinetics of glycosylated recombinant human lymphotoxin (LT) after intravenous bolus injection in rats and compared them with those of tumor necrosis factor (TNF) or LT species. The results are as follows. 1) The mean half-life of glycosylated LT in serum increases for each increase in dose, and the distribution volume (V) and total body clearance [(Cl (total)] tend to decrease for increase in dose. On the other hand, the half-life of TNF also increases for increase in dose, but the V tends to increase for increase in dose and Cl (total) does not change. 2) The glycosylated LT distributes to all organs so far tested except brain, and tends to accumulate to kidney more than other tissues at 6 h after the injection. 3) Nonglycosylated LT produced by E. coli and the glycosylated LT species carrying both N-type and mucin-type sugar moieties (25 kDa LT) have shorter half-lives and higher Cl (total)s than 23 kDa LT carrying N-type sugar moieties alone. The 21 kDa LT, the same species as 23 kDa LT except that it lacks 15 amino acid residues at the N-terminus, disappears much faster than 23 kDa LT and shows higher V and Cl (total). Thus, glycosylated LT shows nonlinear pharmacokinetics like TNF, but the deposition is quite different from that of TNF. The high serum concentration of glycosylated LT depends upon the presence of N-type sugar moieties, but not mucin-type sugar moieties. The N-terminal protein chain of LT also correlates with the serum concentration.
Kawatsu
M
M
Biochemical Research Laboratories, Kanegafuchi Chemical Industry Co., Ltd., Hyogo, Japan.
Takeo
K
K
Kajikawa
T
T
Funahashi
I
I
Asahi
T
T
Kakutani
T
T
Yamashita
T
T
Kawaharada
H
H
Watanabe
K
K
D000596:Amino Acids / Q000493:pharmacokinetics; D000818:Animals; D002241:Carbohydrates / Q000493:pharmacokinetics; D006224:Cricetinae; D006031:Glycosylation; D006801:Humans; D007275:Injections, Intravenous; D008233:Lymphotoxin-alpha / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008970:Molecular Weight; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution
D000596:Amino Acids; D002241:Carbohydrates; D008233:Lymphotoxin-alpha; D011994:Recombinant Proteins