The effects of age on uptake, serum half-life and bioavailability of mouse [D-Leu-4]OB3, a synthetic peptide amide with leptin-like activity, in male C57BL/6J mice.
We have previously shown that the activity of a synthetic peptide amide corresponding to amino acid residues 116-130 of mouse leptin is contained in a restricted sequence at the amino terminus of the peptide, between residues 116 and 122 (Ser-Cys-Ser-Leu-Pro-Glu-Thr). This peptide was named mouse OB3. The potency of OB3 was improved by replacing the L-leucine residue at position four with its D-isomer. Intraperitoneal administration (i.p.) of mouse OB3 or [D-Leu-4]OB3 to ob/ob and db/db mice reduces food intake, body weight gain and serum glucose levels, and enhances insulin sensitivity. These effects of OB3 and [D-Leu-4]OB3 are very pronounced in young mice and diminish with age. In the present study, we measured uptake, serum half-life, and bioavailability of mouse [D-Leu-4]OB3 in mice of different ages. Groups of male C57BL/6J mice, six and 25 weeks of age, were given a single i.p. injection of 1 mg mouse [D-Leu-4]OB3 in PBS. Five, 10, 20, 40, 60, 120, or 180 min after injection, the mice were anesthetized and exsanguinated. Serum samples were prepared and assayed for mouse [D-Leu-4]OB3 content by competitive ELISA. In six week-old mice, the maximum concentration of mouse [D-Leu-4]OB3 was reached in 10 min, and the serum half-life was approximately 52.5 min. In 25 week-old mice, however, mouse [D-Leu-4]OB3 peaked in 5 min, and the serum half-life was approximately 30.6 min. The relative bioavailability of mouse [D-Leu-4]OB3 in six and 25 week-old mice was determined by measuring the area under the uptake curves. Bioavailability of mouse [D-Leu-4]OB3 was approximately 20% greater in six week-old mice than in 25 week-old mice. The results of this study indicate that at least some pharmacokinetic parameters of peptide uptake change as mice age. They also suggest that differences in uptake, serum half-life, and relative bioavailability of mouse [D-Leu-4]OB3 may contribute, at least in part, to the reduced efficacy of bioactive leptin-related peptides we have consistently observed in ob/ob and db/db mice as they age.
Lee
Daniel W
DW
Department of Medicine, Division of Endocrinology and Metabolism, MC 141, Albany Medical College, Albany, NY 12208, USA.
Leinung
Matthew C
MC
Grasso
Patricia
P
D000375:Aging / Q000502:physiology*; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006207:Half-Life; D007274:Injections, Intraperitoneal; D020738:Leptin / Q000008:administration & dosage / Q000819:agonists* / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000008:administration & dosage / Q000819:agonists* / Q000493:pharmacokinetics*; D013237:Stereoisomerism
D020738:Leptin; D010446:Peptide Fragments; C410793:leptin (116-130)