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) 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 (< or = 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 (< or = 0.05 ng/mL) of acid-precipitable radioactivity were detected in plasma after topical application of [125I]rhTGF-beta 1 (1 microgram/kg, 126 microCi/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Safety Evaluation, Genentech, Inc., South San Francisco, California 94080-4990.
Chen
S A
SA
Richardson
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Mora-Worms
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Lucas
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Lewis
D
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Green
J D
JD
Mordenti
J
J
D000287:Administration, Topical; D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D013154:Spleen / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001743:Urinary Bladder / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta