Microdialysis as a tool in pharmacokinetic-pharmacodynamic studies investigating the brain distribution and effect delay of morphine and morphine-6-glucuronide
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
The microdialysis technique was developed as a tool for studying the pharmacokinetic and pharmacodynamicrelationships of morphine and morphine-6-glucronide (M6G). Concentrations of unbound drug in blood andbrain were monitored in order to elucidate the origin of the observed delay in antinociceptive effect in rats.The antinociceptive effect was measured as the response to electrical stimulation of the tail and respiratoryeffects were monitored by measuring the blood gas status. The data analysis was performed in NONMEM andPCNONLIN.
It was shown that in vitro testing is an essential step in the selection of a candidate drug for in vivomicrodialysis. A comparative study of in vivo calibration methods showed no significant difference betweenthe unbound concentration-time profiles obtained with retrodialysis by drug or by calibrator (nalorphine).The delay in antinociceptive effect of morphine in relation to the blood concentration was estimated to havean equilibration half-life of 32 min, which was considerably shorter than the equilibration half-life of 103 minfor M6G. Remaining effect delays of 5 or 53 mitt, respectively, were observed when the effect was related tothe brain extracellular fluid (ECF) concentrations of morphine and M6G. Unexpectedly, the brain ECF:bloodratio for unbound morphine (0.25 ± 0.13) was comparable with the value for M6G (0,22 ± O.O9), indicating theinvolvement of active mechanisms of transport across the blood-brain barrier (BBB) for both compounds.Significantly longer half-lives for morphine and M6G were observed in brain (43 ± 9 and 58 ± 17 min,respectively) than in blood (31 ± 8 and 23 ± 5 min, respectively), Thus, redistribution in the brain is the ratelimiting step for the elimination of both morphine and M6G out of the brain.
Clinical microdialysis of morphine showed a similar pattern to that observed in the animal studies, with asignificantly longer half-life in uninjured (73 min) or injured (77 min) brain tissue, than in blood (28 min) andadipose tissue (27 min).
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2000. , 58 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 221
Research subject Biopharmaceutics
IdentifiersURN: urn:nbn:se:uu:diva-1033ISBN: 91-554-4659-0OAI: oai:DiVA.org:uu-1033DiVA: diva2:160570
2000-03-17, lecture hall B22, Uppsala, Biomedical Centre, Uppsala, 10:15