CAN:s bibliotek

*000      am
*00117859
*008070120|1992|||||||||||e|m||||||||0|eng|d
*020  $a91-554-2960-2$x91-554-2960-2
*1001 $aEkblom, Marianne
*24510$aPharmacokinetic and pharmacodynamic studies of morphine and morphine-3-glucuronide in rats :$bincluding validation and application of microdialysis technique and time dependency of antinociceptive effects
*260  $aUppsala :$bUniv,$c1992$y1992
*300  $a58 s :$bill.
*440 0$aComprehensive summaries of Uppsala dissertations from the Faculty of Pharmacy ;$v100 Acta Universitatis Upsaliensis
*500  $aHärtill 5 uppsatser
*520  $aTolerance development and rebound effect to the antinociceptive effect of morphine were investigated and correlated to morphine pharmacokinetics. Six different rates and five durations of i.v. administration of morphine and two control groups were studied. A combined effect and tolerance model was developed to describe the tolerance development and rebound hyperalgesia. The effect delay was determined by a half-life of 23-28 minutes. Two different rates of tolerance development were estimated, determined by half-lives of 54 +/- 4 minutes and 26 +/- 6 hours. Systematically administered M3G antagonized the antinociceptive effect of morphine, but not to an extent that could fully explain the tolerance development observed after morphine administration. Clearance (Cl) of morphine after a bolus dose was 148 +/- 58 ml/min*kg and after constant rate infusion 108 +/- 32 ml/min*kg (N.S.). Cl of M3G was 12.1 +/- 0.6 ml/min*kg after bolus dose, significantly higher (p less than 0.02) than during infusion, 10.5 +/- 1.7 ml/min*kg. The difference in Cl for the two administrations are probably due to the enterohepatic circulation of morphine and M3G. In a protein binding study the microdialysis technique was compared to equilibrium dialysis for four model drugs. Equal protein binding was estimated for two out of the four drugs. By use of the microdialysis technique and nonlinear regression analysis, the unbound concentrations of morphine in striatum was estimated during steady state morphine concentrations in plasma of 4.2 +/- 1.4 muM. For the different rats the unbound concentration varied between 0.06 and 0.11 muM. A validation of five empirically derived equations used to estimate Cu by non-linear regression was performed by a serum in vitro study and by Monte Carlo simulations.
*650 4$aAnimal
*650 4$aRats
*650 4$aMorphine
*650 4$aNarcotics
*650 4$aGlucuronates
*650 4$aPharmacokinetics
*650 4$aProtein binding
*650 4$aMicrodialysis
*650 4$aPlasma
*653  $aDjurförsök
*653  $aMorfin
*653  $aNarkotika
*653  $aFarmakologi
*852  $hDiss.167
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