studies on the disposition of morphine and morphine 6glucuronide whth partixcular reference to children

Abstract

the objective of these studies was to examine the pharmacokinetics and effects of morphine and its active metabolit,morphine6glucuronide in children and the transport of these compounds by membrane transporters.serum samples were collected from children with cancer receiving morphine.morphine was measured by high performance liquid chromatography and morphine 6glucuronide by enzyme linked immunosorbent assay using methods, wich i modified to optimise sensitivity , specificity and reproducibility . protein binding was determined by equilibrium dialysis. permeability via cell lines MDCKII and MDRPGP was measured in the presence and absence of various transporter inhibitors. on average 34 of morphine was bound in the serum of children. albumin was the principal binding protein. A small proporthin was also bound to alpha1 acid glycoprotein. the serum Ph, and concentratiomns of morphine and palmitic acid affected the degree of morphine protein binding. morphine6glucuronide protein binding in serum of children was around 31 most of it to albumin. for both compounds binding was greater in adults less in children and least in neonates . morphine6glucuronide protein binding was affected by palmitic acid, oleic acid, concentration of the drug and the presence of vincristine and methotrexate.children rapidly metabolised morphine to morphine 6glucuronide with a terminal half life of approximately 2.1and 5.5hour, respectivelty.both compounds crossed a cell monolayer more easily than sucrose.implying an active transport process . morphine permeability was higher than morphine 6glucuronide .althought both were substrates for some transporters. (including pglycorprotein and digoxin related), others (notably dglucose sensitive transporters)affected only morphine 6glucuronide transport. nither compound was a substate for the probenecid sensitive anionic transporter.