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

Recombinant human transforming growth factor beta (rhTGF-beta(1)) enha nces the healing process after topical application to various animal w ound 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 rapi d (<11 min), regardless of whether radiolabeled or unlabeled rhTGF-bet a(1) was used. The terminal half-life was long (163 min) when the test material was radioiodinated and administered as a trace dose and rela tively short (less than or equal to 61 min) when given at high doses a nd assayed by ELISA. Analysis of plasma radioactivity by SDS-PAGE reve aled a time-dependent clearance of the 25-kDa parent molecule without a significant appearance of lower molecular weight radiolabeled metabo lites. The majority of the radioactivity was associated with highly pe rfused organs, known iodide elimination pathways, and the thyroid at 1 and 8 hr after iv injection. After topical administration of a high d ose (0.8 mg/kg), no immunoreactive TGF-beta(1) was detectable in plasm a samples taken over a 48-hr period. However, trace amounts (less than or equal to 0.05 ng/mL) of acid-precipitable radioactivity were detec ted 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-b eta(1) persisted intact (25 kDa) at the wound site 24 hr after applica tion. 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 sin gle topical dose of rhTGF-beta(1) to a wound, and the intact molecule persisted at the wound site.