Pharmacokinetics and Tissue Distribution of Recombinant Human Transforming Growth Factor Beta1 After Topical and Intravenous Administration in Male Rats

Recombinant human transforming growth factor beta (rhTGF-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-₁ for wound healing indications. Rats received radioiodinated or unlabeled rhTGF-₁ as an intravenous (iv) bolus or as a topical formulation applied to a full thickness wound. Plasma concentrations of TGF-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 radi-olabeled or unlabeled rhTGF-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 (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-₁ was detectable in plasma samples taken over a 48-hr period. However, trace amounts (0.05 ng/mL) of acid-precipitable radioactivity were detected in plasma after topical application of ¹²⁵I]rhTGF-₁ (1 µg/kg, 126 µCi/kg). A significant portion (35%) of the ¹²⁵I]rhTGF-₁ persisted intact (25 kDa) at the wound site 24 hr after application. In conclusion, rhTGF-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-₁ to a wound, and the intact molecule persisted at the wound site.