Abstract
Pharmacokinetic and biodistribution studies were conducted in rats on a novel serine protease inhibitor, LEX 032, that was radiolabeled with 131I by the Bolton-Hunter reagent. LEX 032, a genetically engineered recombinant human nonglycosylated serpin, has been shown to have antiinflammatory properties in a number of animal models of inflammation and reperfusion injury. When131I-LEX 032 was injected intravenously, a rapid whole body clearance of radioactivity was seen. Blood clearance followed a similar pattern. Forty-eight hours postinjection, 2.00 ± 0.65% of the administered dose remained in the body. Greater than 59% of the radioactivity was excreted in the urine within the first 24 hr. Little radioactivity was found in the feces. With the exception of the thyroid, no significant organ-related uptake was noted. Radioactivity in the liver peaked at 20 min postinjection, with 1.00 ± 0.13% administered dose/g and ∼10% administered dose in the whole liver. At 1 hr, uptake in the kidney (9.30 ± 1.52% administered dose/g) was the highest among all tissues, except for the thyroid. Gamma camera images were consistent with the biodistribution pattern. Pharmacokinetics and biodistribution were not affected by the dose of LEX 032 and were quite different from those of glycosylated wild type antichymotrypsin. These data indicate that LEX 032 exhibits the pharmacokinetics expected of a nonglycosylated 45 kDa protein.
Footnotes
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Send reprint requests to: Dr. Howard Sands, Sparta Pharmaceuticals, Inc., 111 Rock Road, Horsham, PA 19044.
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↵1 Present address: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591.
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This work was partially supported by SBIR AI-38659-01 from the National Institute of Allergy and Infectious Diseases.
- Abbreviations used are::
- α1-PI
- α1 protease inhibitor
- ACT
- antichymotrypsin
- SDS
- sodium dodecyl sulfate
- PAGE
- polyacryamide gel electrophoresis
- % ad. dose
- percent administered dose
- Received June 20, 1996.
- Accepted January 29, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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