title: Pharmacokinetics in chimpanzees of recombinant human tissue-type plasminogen activator produced in mouse C127 and Chinese hamster ovary cells.
abstract: 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.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: R
authors.initials: R
authors.lastname: Hori
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.forename: J
authors.initials: J
authors.lastname: Tsuji
authors.forename: N
authors.initials: N
authors.lastname: Shimizu
authors.forename: S
authors.initials: S
authors.lastname: Noma
authors.forename: J
authors.initials: J
authors.lastname: Suzuki
authors.forename: D J
authors.initials: DJ
authors.lastname: Livingston
authors.forename: S M
authors.initials: SM
authors.lastname: Richards
authors.forename: L D
authors.initials: LD
authors.lastname: Keyes
mesh_terms: 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*
chemical_list: D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator