Pharmacokinetics in chimpanzees of recombinant human tissue-type plasminogen activator produced in mouse C127 and Chinese hamster ovary cells.
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 alpha-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-alpha-galactosyl antibody. The anti-alpha-galactosyl antibody level in plasma decreased in association with the plasma levels of t-PA(C127) but was unaffected by t-PA(CHO) levels.
Tanigawara
Y
Y
Department of Pharmacy, Kyoto University Hospital, Japan.
Hori
R
R
Okumura
K
K
Tsuji
J
J
Shimizu
N
N
Noma
S
S
Suzuki
J
J
Livingston
D J
DJ
Richards
S M
SM
Keyes
L D
LD
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D008297:Male; D051379:Mice; D002679:Pan troglodytes; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics*
D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator