title: Naloxone affects both pharmacokinetics and pharmacodynamics of morphine. Application of direct correlation analysis.
abstract: Direct correlation analyses between the distribution of morphine (pharmacokinetics) and the biochemical effects of the drug on monoamine metabolism (pharmacodynamics) are reported for dissected regions of the brain. Determinations of morphine and monoamine-related substances were carried out in the same sample by high performance liquid chromatography with electrochemical detection. Naloxone, an antagonist of morphine, significantly shortened the biological half lives of morphine in both the blood and brain tissue. Such pharmacokinetic behavior appeared to be related to the contractive effect of morphine on the bile duct, and naloxone facilitated the excretion of morphine via this route. In the striatum, significant correlations were observed between the concentrations of the metabolites of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and morphine with a shift to the right in the concentration-response curve on naloxone treatment indicating competitive antagonism. While significant correlations were also observed in this brain region for the metabolites of noradrenaline, 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), and 5-hydroxytryptamine, 5-hydroxyindoleacetic acid (5-HIAA), a shift to the right did not occur. Significant correlations and shifts were noted for DOPAC, HVA and MOPEG in the hypothalamus. However, no correlation was found between the concentrations of 5-HIAA and morphine in this region. In other regions such as the hippocampus and medulla oblongata, similar correlations and shifts were not observed for MOPEG and 5-HIAA or for DOPAC and HVA.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shibanoki
authors.forename: T
authors.initials: T
authors.lastname: Kubo
authors.forename: M
authors.initials: M
authors.lastname: Kogure
authors.forename: K
authors.initials: K
authors.lastname: Ishikawa
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000378:metabolism; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013223:Statistics as Topic; D013448:Sulfobromophthalein / Q000493:pharmacokinetics
chemical_list: D013448:Sulfobromophthalein; D015102:3,4-Dihydroxyphenylacetic Acid; D009270:Naloxone; D008734:Methoxyhydroxyphenylglycol; D006897:Hydroxyindoleacetic Acid; D009020:Morphine; D006719:Homovanillic Acid