Pharmacokinetics of novel hexapeptides with neurotensin activity in rats.
A high-performance liquid chromatographic method to determine (Me)Arg-Lys-Pro-Trp-tert-Leu-Leu (NT-2) with neurotensin (NT) activity in rat plasma was developed and a pharmacokinetic study was performed in rats. Quantitative analysis with high reproducibility was achieved for NT-2 over the concentration range of 1.14-500 ng/ml. (Me)Arg-Lys-Pro-Trp-tert-Leu-Leu-OEt (NT-1) was rapidly hydrolyzed to NT-2 in rat plasma at 37 degrees C. This degradation of NT-1 was observed as a pseudo first-order reaction, and the pseudo first-order rate constant was calculated to be 7.26 min-1 (t1/2 = 0.095 min). The pharmacokinetic profiles of NT-2 after intravenous administration of NT-1 at doses of 0.1 and 0.3 mg/kg were compatible with that of NT-2 after intravenous administration of NT-2 at 0.5 mg/kg. Range of the half-life of the terminal phase (t1/2 beta) of NT-2 was 0.36-0.53 h. The absolute bioavailabilities after oral administrations of NT-1 and NT-2 at a dose of 20 mg/kg were 0.61 +/- 0.17 (mean +/- S.E.) and 0.19 +/- 0.08%, respectively. It was found that NT-1 was more suitable for oral administration than NT-2.
Machida
R
R
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Tokumura
T
T
Tsuchiya
Y
Y
Sasaki
A
A
Abe
K
K
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009496:Neurotensin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results
D009842:Oligopeptides; C068951:methyl(arginyl)-lysyl-prolyl-tryptophyl-tert-leucyl-leucine; C068195:methylarginyl-lysyl-prolyl-tryptophyl-tert-leucyl-leucyl-ethyl ester; D009496:Neurotensin