RT Journal Article
SR Electronic
T1 Tissue Disposition and Pharmacokinetics of Recombinant Human Nerve Growth Factor after Acute and Chronic Subcutaneous Administration in Monkeys
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 598
OP 607
VO 28
IS 5
A1 Cindy B. Nguyen
A1 Louise Harris
A1 Éva Szönyi
A1 Sharon A. Baughman
A1 Victoria G. Hale
A1 Noël O. Dybdal
A1 Michael D. Sadick
A1 Enrique Escandón
YR 2000
UL http://dmd.aspetjournals.org/content/28/5/598.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics