Pharmacokinetics in Chimpanzees of Recombinant Human Tissue-Type Plasminogen Activator Produced in Mouse C127 and Chinese Hamster Ovary Cells

• Published in: Chemical & pharmaceutical bulletin Vol. 38; no. 2; pp. 517 - 522
• Main Authors: TANIGAWARA, Yusuke, HORI, Ryohei, OKUMURA, Kazuo, TSUJI, Jun-ichi, SHIMIZU, Norihide, NOMA, Seiji, SUZUKI, Junko, LIVINGSTON, David J., RICHARDS, Susan M., KEYES, Lynne D., COUCH, Ronald C., ERICKSON, Mary K.
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1990; Maruzen
• Subjects: Animals; anti-α-galactosyl antibody; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Cell Line; Cells, Cultured; chimpanzee; Cricetinae; Cricetulus; Female; Male; Medical sciences; Mice; moment analysis; Pan troglodytes; pharmacokinetics; Pharmacology. Drug treatments; population pharmacokinetics; Recombinant Proteins - pharmacokinetics; recombinant tissue plasminogen activator; tissue plasminogen activator; Tissue Plasminogen Activator - pharmacokinetics; Intravenous administration; Monkey; Plasminogen activator; Glycoproteins; Bioavailability; Clearance; Blood; Blood plasma; Vertebrata; Mammalia; Structure activity relation; Animal; Interindividual comparison; Primates; Carbohydrate; Pharmacokinetics
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.38.517

Pharmacokinetics of recombinant tissue-type plasminogen activator (rt-PA) produced in mouse C127 cells (t-PA(C127)) and Chinese hamster ovary cells (t-PA(CHO)) was investigated in chimpanzees. rt-PA was administered via a constant rate i.v. infusion for 60 min, and t-PA concentration and activity in plasma were measured during and after infusion. The noncompartmental parameters were calculated according to the moment analysis method, and a population pharmacokinetic analysis was performed to obtain the mean and interindividual variability of the pharmacokinetic parameters. The mean residence time of t-PA(C127) was significantly longer and the total body clearance was significantly less than that of t-PA(CHO). t-PA(C127) has an α-galactosyl moiety in its carbohydrate chains, whereas such a structure is not found in t-PA(CHO). These results demonstrate that two preparations of rt-PA's with different carbohydrate structures show different pharmacokinetics, and suggest that the carbohydrate structure can affect the efficiency of hepatic uptake of t-PA. A possible mechanism is an interaction of t-PA(C127) with the natural anti-α-galactosyl antibody. The anti-α-galactosyl antibody level in plasma decreased in association with the plasma levels of t-PA(C127) but was unaffected by t-PA(CHO) levels.