Tissue disposition and pharmacokinetics of recombinant human nerve growth factor after acute and chronic subcutaneous administration in monkeys.
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 microg/kg of trace (125)I-labeled recombinant human nerve growth factor was dosed. Histological analysis of emulsion-microautoradiography indicated that specific (125)I-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 (125)I-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 microg/kg doses in monkeys is capable of accessing and localizing in the target tissues.
Nguyen
C B
CB
Department of Pharmacokinetics-Metabolism, Genentech, Inc., South San Francisco, California 94080, USA.
Harris
L
L
Szönyi
E
E
Baughman
S A
SA
Hale
V G
VG
Dybdal
N O
NO
Sadick
M D
MD
Escandón
E
E
D000818:Animals; D019540:Area Under Curve; D001345:Autoradiography; D016466:CHO Cells; D006224:Cricetinae; D003928:Diabetic Nephropathies / Q000188:drug therapy; D004591:Electrophoresis, Polyacrylamide Gel; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D007279:Injections, Subcutaneous; D007457:Iodine Radioisotopes; D008252:Macaca fascicularis; D008297:Male; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011233:Precipitin Tests; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution
D007457:Iodine Radioisotopes; D009414:Nerve Growth Factors; D011994:Recombinant Proteins