Pharmacokinetic evidence for the long-lasting effect of nor-binaltorphimine, a potent kappa opioid receptor antagonist, in mice.
Nor-binaltorphimine (nor-BNI) is kappa opioid receptor (KOR) antagonist with the extremely long duration in mice analgesic assay, in vivo. For the evaluation of long-lasting effect of nor-BNI, brain content and serum concentration of nor-BNI were quantified in comparison with those of naloxone (a short-acting non-specific opioid receptor antagonist) by high-performance liquid chromatography with electrochemical detector in mice. After concomitant administration (20 mg/kg, s.c.) of nor-BNI and naloxone, nor-BNI in brain and serum showed biphasic elimination, with a rapid phase for 0.75-4 h and a slow phase for 4-48 h. Elimination rate in brain was slower than that of serum. Naloxone in brain and serum was detected for 3 h and 4 h, respectively. The brain/serum ratio of nor-BNI gradually increased over 0.75-48 h, while that of naloxone rapidly declined. After concomitant administration (30 mg/kg, s.c.) of nor-BNI and naloxone, brain nor-BNI was detected in all mice from day 1 to day 21 and in two of six mice at day 28, while serum nor-BNI was detected in all mice at day 1, three of seven at day 3 and one of six at day 7. After that, serum nor-BNI was not detected. Naloxone in brain and serum was not detected at day 1. These results provide pharmacokinetic support for the long-lasting antagonistic effects of nor-BNI.
Department of Pharmacology, Wakayama Medical University, Wakayama-City, Wakayama 641-8509, Japan. Electronic address: kishioka@wakayama-med.ac.jp.
Shiroh
S
Kishioka
Norikazu
N
Kiguchi
Yuka
Y
Kobayashi
Chizuko
C
Yamamoto
Fumihiro
F
Saika
Naoki
N
Wakida
Mei-Chuan
MC
Ko
James H
JH
Woods
D000818:Animals; D001921:Brain / Q000378:metabolism; D008297:Male; D051379:Mice; D009270:Naloxone / Q000097:blood / Q000493:pharmacokinetics; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors; D013997:Time Factors
D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone
Brain content; HPLC-ECD; Naloxone; Nor-BNI; Pharmacokinetics