PHARMACOKINETICS AND TISSUE DISTRIBUTION OF RECOMBINANT HUMAN TRANSFORMING GROWTH-FACTOR BETA(1) AFTER TOPICAL AND INTRAVENOUS ADMINISTRATION IN MALE-RATS

被引:50
作者
ZIONCHECK, TF [1 ]
CHEN, SA [1 ]
RICHARDSON, L [1 ]
MORAWORMS, M [1 ]
LUCAS, C [1 ]
LEWIS, D [1 ]
GREEN, JD [1 ]
MORDENTI, J [1 ]
机构
[1] GENENTECH INC, DEPT MED & ANALYT CHEM, S SAN FRANCISCO, CA 94080 USA
关键词
RECOMBINANT HUMAN TRANSFORMING GROWTH FACTOR; BETA(1); WOUND-HEALING; PHARMACOKINETICS; PLASMA-BASED ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA); TISSUE DISTRIBUTION;
D O I
10.1023/A:1018995005775
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Recombinant human transforming growth factor beta (rhTGF-beta(1)) enhances the healing process after topical application to various animal wound models. A detailed pharmacokinetic and tissue distribution study was performed to support the clinical development of rhTGF-beta(1) for wound healing indications. Rats received radioiodinated or unlabeled rhTGF-beta(1) as an intravenous (iv) bolus or as a topical formulation applied to a full thickness wound. Plasma concentrations of TGF-beta(1) were estimated from TCA-precipitable radioactivity or were measured by ELISA. Following iv administration, the initial half-life was rapid (<11 min), regardless of whether radiolabeled or unlabeled rhTGF-beta(1) was used. The terminal half-life was long (163 min) when the test material was radioiodinated and administered as a trace dose and relatively short (less than or equal to 61 min) when given at high doses and assayed by ELISA. Analysis of plasma radioactivity by SDS-PAGE revealed a time-dependent clearance of the 25-kDa parent molecule without a significant appearance of lower molecular weight radiolabeled metabolites. The majority of the radioactivity was associated with highly perfused organs, known iodide elimination pathways, and the thyroid at 1 and 8 hr after iv injection. After topical administration of a high dose (0.8 mg/kg), no immunoreactive TGF-beta(1) was detectable in plasma samples taken over a 48-hr period. However, trace amounts (less than or equal to 0.05 ng/mL) of acid-precipitable radioactivity were detected in plasma after topical application of [I-125]rhTGF-beta(1) (1 mu g/kg, 126 mu Ci/kg). A significant portion (35%) of the [I-125]rhTGF-beta(1) persisted intact (25 kDa) at the wound site 24 hr after application. In conclusion, rhTGF-beta(1) was rapidly cleared after iv bolus administration and distributed primarily to the liver, lungs, kidney, and spleen. Little systemic exposure was observed after applying a single topical dose of rhTGF-beta(1) to a wound, and the intact molecule persisted at the wound site.
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页码:213 / 220
页数:8
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