Abstract
In this study, we have characterized the metabolism, tissue disposition, excretion routes, and plasma pharmacokinetics of recombinant human nerve growth factor after single and multiple s.c. administration in male cynomolgus monkeys. Unlabeled nerve growth factor (NGF; 2 mg/kg) was administered three times a week for 4 weeks and a full pharmacokinetic profile was obtained for doses 1 and 12. For the tissue distribution studies, 0.8 μg/kg of trace125I-labeled recombinant human nerve growth factor was dosed. Histological analysis of emulsion-microautoradiography indicated that specific 125I-NGF labeling was confined to sections of nerves most frequently localized adjacent to large vessels in sections of kidney, spleen, liver, and salivary gland. A small percentage of large neurons within the sympathetic ganglia were intensely labeled, as well as large neurons within the dorsal root ganglia. We found an increased disposition of 125I-NGF in parts of the peripheral nervous system (including sympathetic ganglia) from 8 to 24 h postdose. In contrast, radioactivity in most non-neuronal tissues declined. This suggests specific uptake in these target tissues known to express specific receptors for NGF. We also identified changes in pharmacokinetic parameters after single versus chronic s.c. administration. These studies demonstrated that s.c. administration of NGF at 0.8 μg/kg doses in monkeys is capable of accessing and localizing in the target tissues.
Footnotes
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Send reprint requests to: Enrique Escandón, Ph.D., Dept. of Pharmacokinetics and Metabolism, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. E-mail: quique{at}gene.com
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This work was supported by Genentech, Inc.
- Abbreviations used are::
- NGF
- nerve growth factor
- rhNGF
- recombinant human nerve growth factor
- trkA
- receptor tyrosine kinase
- PK
- pharmacokinetic
- PAGE
- polyacrylamide gel electrophoresis
- ELISA
- enzyme-linked immunosorbent assay
- KIRA
- kinase receptor activation assay
- TCA
- trichloroacetic acid
- DRG
- dorsal root ganglia
- CNS
- central nervous system
- PNS
- peripheral nervous system
- Cmax
- maximum observed rhNGF plasma concentration
- Vz/F
- central volume of distribution
- Received June 1, 1999.
- Accepted January 27, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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