Master of Science / Department of Clinical Sciences / Elizabeth Davis / Differences in pharmacokinetics and drug disposition exist between young and adult animals which become especially important for drugs with a narrow therapeutic index. While the pharmacokinetics and plasma concentrations of intravenous lidocaine have been studied in adult horses, determination of the disposition in foals is necessary before appropriate clinical use can be determined. This study examined the disposition of intravenous lidocaine in healthy (phase I) and hospitalized (phase II) foals. Phase I consisted of 6 healthy 4-10 week old foals administered a 6-hour intravenous lidocaine infusion. Phase II consisted of 8 hospitalized foals (2-136 days old) administered intravenous lidocaine. A bolus (1.3 mg/kg) of lidocaine was administered intravenously to all foals followed by a 50 µg/kg/min infusion. Plasma lidocaine and monoethylglycinexylidide (MEGX) concentrations were determined. In phase I, plasma lidocaine concentrations remained below the suggested adult target range of 1-2 µg/mL with MEGX concentrations approximately half that of the parent drug. Total body clearance of lidocaine was 72.2 ± 7.8 mL/min/kg, elimination half-life (t₁/₂) was 26.3 ± 3.7 min, peak concentration (C[subscript]m[subscript]a[subscript]x) was 0.79 ± 0.07 µg/mL, and the volume of distribution (V[subscript]d) was 1.8 ± 0.4 L/kg. The C[subscript]m[subscript]a[subscript]x for MEGX was 0.36 ± 0.11 µg/mL, t₁/₂ was 60 ± 6 min and time to peak concentration (T[subscript]m[subscript]a[subscript]x) was 279.6 ± 90.3 min. In phase II, the severely compromised foals that were eventually euthanized had the largest fluctuations in plasma lidocaine and MEGX concentrations; foals that were discharged from the hospital had plasma concentrations below the target adult range similar to foals in phase I. In conclusion, despite low plasma lidocaine concentrations, the clinical benefits observed in foals may be due to the presence of metabolites. Further research in a larger population of unhealthy foals is required before comprehensive dosing recommendations can be made.

O bloqueio peridural com lidocaína, bupivacaína e fentanila representa um dos procedimentos anestésicos mais utilizados em obstetrícia, fato que justifica o estudo farmacocinético destes fármacos nessas condições. Os objetivos deste trabalho foram investigar a farmacocinética e a análise da transferência placentária da lidocaína e seu metabólito monoetilglicinaxilidida (MEGX) em gestantes normais e com diabetes mellitusgestacional (DMG), submetidas a anestesia peridural com lidocaína, bem como, avaliar a influência das alteraçõesfisiopatológicas da diabetes gestacional sobre os parâmetros farmacocinéticos desta droga e de seu metabólito. Foram avaliadas dez gestantes normais (grupo 1) e seis gestantes com DMG (grupo 2), todas de termo. Todas receberam cloridrato de lidocaína a 2% sem vasoconstrictor, em dose pré-determinada, por via loco-regional peridural. Na seqüência foram coletadas amostras sanguíneas maternas nos tempos 1 minuto, 5, 15, 30, 45, 60, 120, 240, 360, 480, 600, 720 e 840 minutos e amostras de sangue do espaço interviloso placentário, de artéria e veia umbilical para determinação das concentraçõesde lidocaína e MEGX por cromatografia e a análise farmacocinética. Com base nas concentrações maternas e fetais no momento do nascimento foram determinadas as relações entre os compartimentos maternos e fetais destes fármacos e taxa de extração fetal. As medianas dos parâmetros farmacocinéticos da lidocaína para os grupos 1 e 2 foram, respectivamente: Cmax 879,11 e 1145,58 ng/mL, t1/2 ?202,09 e 272,16 min, ?0,0034 e 0,0025 min -1 , AUC 0-? 256013,50 e 455950,97 ng.min/mL, Cl/f/kg 10,61 e 5,64 mL/min/kg, Vd/f/kg 3255,24 e 2188,304 mL/kg. As medianas dos parâmetros farmacocinéticos do MEGX para os grupos 1 e 2 foram, respectivamente: Cmax 82,71 e 141,38 ng/mL, Tmax 44,71 e 193,14 min, t1/2 ?7,64 e 59,77 min, ?0,097 e 0,012 min -1 , t1/2 ?247,28 e 492,20 min, ? 0,0028 e 0,0016 min -1 , AUC 0-? 29906,71 e 108229,19 ng.min/mL. A mediana do tempo de latência entre a administração da droga e o nascimento foi de 28,5 min e 28 min nos grupos 1 e 2, respectivamente. As medianas das relações entre os compartimentos maternos e fetais para a lidocaína nos grupos 1 e 2 foram, respectivamente: relação veia umbilical / sangue materno periférico: 0,60 e 0,46; relação espaço interviloso / materna: 1,01 e 0,88; relação artéria umbilical/ veia umbilical: 0,77 e 0,91; relação veia umbilical / espaço interviloso: 0,53 e 0,51. As medianas nos grupos 1 e 2 para o MEGX foram, respectivamente: relação feto / materna 0,43 e 0,97; relação espaço interviloso / materna: 0,64 e 0,90; relação artéria umbilical/ veia umbilical: 1,09 e 0,99; relação veia umbilical / espaço interviloso: 0,55 e 0,78. Os dados desse estudo permitem concluir que o clearanceaparente da lidocaína e do MEGX mostraram-se reduzidos nas pacientes diabéticas em relação às normais, sugerindo que o DMG inibe as isoformas CYP1A2 / CYP3A4, responsáveis pela metabolização desse fármaco e de seus metabólitos. O DMG não afetou o transporte passivo da lidocaína, porém, interferiu na transferência transplacentária do MEGX, atuando como um mecanismo facilitador para o transporte do mesmo. / The epidural blockade with lidocaine, bupivacaine and fentanyl represents one of the anesthetic procedures most frequently usedin obstetrics, a fact that justifies the pharmacokinetic study of these drugs in these conditions. The objectives of the present study were to investigate the pharmacokinetics and placental transfer of lidocaine and its metabolite monoetilglicinaxilidida (MEGX) in normal parturients and with gestational diabetes mellitus (GDM), whose pregnancies were resolved by caesarean section with epidural anesthesia and to evaluate the influence of GDM on the pharmacokinetic parameters of this drug and its metabolite. Ten parturients considered to be normal in clinical and laboratory terms (group 1) and six pregnant with GDM (group 2) with term gestation were evaluated.All pregnant women received 2% lidocaine hydrochloride without a vasoconstrictor by epidural rote, with pre-determined dose. Maternal blood samples were collected at 1, 5, 15, 30, 45, 60, 120, 240, 360, 480, 600, 720, and 840 minutes together with blood samples from the placental interviloso space, umbilical artery and umbilical vein for determination of the concentrations of lidocaine and MEGX by chromatography and the pharmacokinetic analysis. The relationship between maternal and fetal concentrationsand ratio of fetal extraction of the drug were determined on the basis of concentrationsat the time of birth. The median of the pharmacokinetic parameters of lidocaine for groups 1 and 2 respectively were: Cmax 879.11 and 1145.58 ng/mL; t1/2 ?202,09 and 272,16 min, ?0,0034 and 0,0025 min -1 , AUC 0-? 256013,50 and 455950,97 ng.min/mL, Cl/f/kg 10,61 and 5,64 mL/min/kg, Vd/f/kg 3255,24 and 2188,304 mL/kg. The median of the pharmacokinetic parameters of MEGX for groups 1 and 2 respectively were: Cmax 82,71 and 141,38 ng/mL, Tmax 44,71 and 193,14 min, t1/2 ?7,64 and 59,77 min, ?0,097 and 0,012 min -1 , t1/2 ? 247,28 and 492,20 min, ?0,0028 and 0,0016 min -1 , AUC 0-? 29906,71 and 108229,19 ng.min/mL. The latency between drug administration and birth was 28.5 min and 28 min in groups 1 and 2, respectively. The medians of the relationship between maternal and fetal compartments for lidocaine in groups 1 and 2 were, respectively: the fetus / mother ratio (umbilical vein / maternal peripheral blood): 0.60 and 0.46; interviloso space / mother ratio: 1.01 and 0.88; umbilical artery / umbilical vein ratio: 0.77 and 0.91; umbilical vein / interviloso space ratio: 0.53 and 0.51. The medians in groups 1 and 2 for the MEGX were, respectively: the fetus / maternal ratio 0.43 and 0.97; interviloso space / mother ratio: 0.64 and 0.90; umbilical artery / umbilical vein ratio: 1.09 and 0.99; umbilical vein / interviloso space ratio: 0.55 and 0.78. The data of this study suggest that the lidocaine and MEGX clearance have been reduced in diabetic patients in relation to the normal ones, suggesting that the GDM inhibits the isoforms CYP1A2 / CYP3A4, responsiblefor the metabolism of the drug and its metabolites. The DMG did not affect the passive transport of lidocaine, however, facilitated the placental transfer of MEGX.

O bloqueio peridural com lidocaína, bupivacaína e fentanila representa um dos procedimentos anestésicos mais utilizados em obstetrícia, fato que justifica o estudo farmacocinético destes fármacos nessas condições. Os objetivos deste trabalho foram investigar a farmacocinética e a análise da transferência placentária da lidocaína e seu metabólito monoetilglicinaxilidida (MEGX) em gestantes normais e com diabetes mellitusgestacional (DMG), submetidas a anestesia peridural com lidocaína, bem como, avaliar a influência das alteraçõesfisiopatológicas da diabetes gestacional sobre os parâmetros farmacocinéticos desta droga e de seu metabólito. Foram avaliadas dez gestantes normais (grupo 1) e seis gestantes com DMG (grupo 2), todas de termo. Todas receberam cloridrato de lidocaína a 2% sem vasoconstrictor, em dose pré-determinada, por via loco-regional peridural. Na seqüência foram coletadas amostras sanguíneas maternas nos tempos 1 minuto, 5, 15, 30, 45, 60, 120, 240, 360, 480, 600, 720 e 840 minutos e amostras de sangue do espaço interviloso placentário, de artéria e veia umbilical para determinação das concentraçõesde lidocaína e MEGX por cromatografia e a análise farmacocinética. Com base nas concentrações maternas e fetais no momento do nascimento foram determinadas as relações entre os compartimentos maternos e fetais destes fármacos e taxa de extração fetal. As medianas dos parâmetros farmacocinéticos da lidocaína para os grupos 1 e 2 foram, respectivamente: Cmax 879,11 e 1145,58 ng/mL, t1/2 ?202,09 e 272,16 min, ?0,0034 e 0,0025 min -1 , AUC 0-? 256013,50 e 455950,97 ng.min/mL, Cl/f/kg 10,61 e 5,64 mL/min/kg, Vd/f/kg 3255,24 e 2188,304 mL/kg. As medianas dos parâmetros farmacocinéticos do MEGX para os grupos 1 e 2 foram, respectivamente: Cmax 82,71 e 141,38 ng/mL, Tmax 44,71 e 193,14 min, t1/2 ?7,64 e 59,77 min, ?0,097 e 0,012 min -1 , t1/2 ?247,28 e 492,20 min, ? 0,0028 e 0,0016 min -1 , AUC 0-? 29906,71 e 108229,19 ng.min/mL. A mediana do tempo de latência entre a administração da droga e o nascimento foi de 28,5 min e 28 min nos grupos 1 e 2, respectivamente. As medianas das relações entre os compartimentos maternos e fetais para a lidocaína nos grupos 1 e 2 foram, respectivamente: relação veia umbilical / sangue materno periférico: 0,60 e 0,46; relação espaço interviloso / materna: 1,01 e 0,88; relação artéria umbilical/ veia umbilical: 0,77 e 0,91; relação veia umbilical / espaço interviloso: 0,53 e 0,51. As medianas nos grupos 1 e 2 para o MEGX foram, respectivamente: relação feto / materna 0,43 e 0,97; relação espaço interviloso / materna: 0,64 e 0,90; relação artéria umbilical/ veia umbilical: 1,09 e 0,99; relação veia umbilical / espaço interviloso: 0,55 e 0,78. Os dados desse estudo permitem concluir que o clearanceaparente da lidocaína e do MEGX mostraram-se reduzidos nas pacientes diabéticas em relação às normais, sugerindo que o DMG inibe as isoformas CYP1A2 / CYP3A4, responsáveis pela metabolização desse fármaco e de seus metabólitos. O DMG não afetou o transporte passivo da lidocaína, porém, interferiu na transferência transplacentária do MEGX, atuando como um mecanismo facilitador para o transporte do mesmo. / The epidural blockade with lidocaine, bupivacaine and fentanyl represents one of the anesthetic procedures most frequently usedin obstetrics, a fact that justifies the pharmacokinetic study of these drugs in these conditions. The objectives of the present study were to investigate the pharmacokinetics and placental transfer of lidocaine and its metabolite monoetilglicinaxilidida (MEGX) in normal parturients and with gestational diabetes mellitus (GDM), whose pregnancies were resolved by caesarean section with epidural anesthesia and to evaluate the influence of GDM on the pharmacokinetic parameters of this drug and its metabolite. Ten parturients considered to be normal in clinical and laboratory terms (group 1) and six pregnant with GDM (group 2) with term gestation were evaluated.All pregnant women received 2% lidocaine hydrochloride without a vasoconstrictor by epidural rote, with pre-determined dose. Maternal blood samples were collected at 1, 5, 15, 30, 45, 60, 120, 240, 360, 480, 600, 720, and 840 minutes together with blood samples from the placental interviloso space, umbilical artery and umbilical vein for determination of the concentrations of lidocaine and MEGX by chromatography and the pharmacokinetic analysis. The relationship between maternal and fetal concentrationsand ratio of fetal extraction of the drug were determined on the basis of concentrationsat the time of birth. The median of the pharmacokinetic parameters of lidocaine for groups 1 and 2 respectively were: Cmax 879.11 and 1145.58 ng/mL; t1/2 ?202,09 and 272,16 min, ?0,0034 and 0,0025 min -1 , AUC 0-? 256013,50 and 455950,97 ng.min/mL, Cl/f/kg 10,61 and 5,64 mL/min/kg, Vd/f/kg 3255,24 and 2188,304 mL/kg. The median of the pharmacokinetic parameters of MEGX for groups 1 and 2 respectively were: Cmax 82,71 and 141,38 ng/mL, Tmax 44,71 and 193,14 min, t1/2 ?7,64 and 59,77 min, ?0,097 and 0,012 min -1 , t1/2 ? 247,28 and 492,20 min, ?0,0028 and 0,0016 min -1 , AUC 0-? 29906,71 and 108229,19 ng.min/mL. The latency between drug administration and birth was 28.5 min and 28 min in groups 1 and 2, respectively. The medians of the relationship between maternal and fetal compartments for lidocaine in groups 1 and 2 were, respectively: the fetus / mother ratio (umbilical vein / maternal peripheral blood): 0.60 and 0.46; interviloso space / mother ratio: 1.01 and 0.88; umbilical artery / umbilical vein ratio: 0.77 and 0.91; umbilical vein / interviloso space ratio: 0.53 and 0.51. The medians in groups 1 and 2 for the MEGX were, respectively: the fetus / maternal ratio 0.43 and 0.97; interviloso space / mother ratio: 0.64 and 0.90; umbilical artery / umbilical vein ratio: 1.09 and 0.99; umbilical vein / interviloso space ratio: 0.55 and 0.78. The data of this study suggest that the lidocaine and MEGX clearance have been reduced in diabetic patients in relation to the normal ones, suggesting that the GDM inhibits the isoforms CYP1A2 / CYP3A4, responsiblefor the metabolism of the drug and its metabolites. The DMG did not affect the passive transport of lidocaine, however, facilitated the placental transfer of MEGX.

Die Arbeit befasst sich mit Methoden der Erfassung metabolischer Funktion einer dynamischen Zellkultur in Bioreaktoren zur klinischen Verwendung als Leberunterstützungssystem. Der Fokus liegt auf der Etablierung von Tests zur Qualitätssicherung als effiziente In- Prozess Kontrollen während der Bereitstellungsphase der Zellkulturen. Weitere Ziele sind ein Beitrag zu Wirksamkeitsnachweis und zur Charakterisierung des Systems im Rahmen von Zulassungen als "Biologic". Bei der experimentellen Untersuchung unter Verwendung von Leberzellkulturen aus porcinen Organen wurden der Lidocain- MEGX Test, die Elimination von Galaktose und Sorbitol sowie die Elimination von Ammoniak und die Synthese von Harnstoff, Lactat und Albumin berücksichtigt. Dies erfolgte mittels Bolus- und Fliessgleichgewichtsuntersuchungen sowie Konzentrationsbestimmungen. Die Ergebnisse zeigten für alle Parameter einen hochsignifikanten Unterschied zu Zellfreien Bioreaktoren, sowie einen typischen Verlauf, der in eine initiale Adhäsionsphase, eine stabile Kulturphase und eine darauf folgende erweiterte Phase mit langsamer Abschwächung der Zellleistungen gegliedert werden kann. Die Parameter erwiesen sich prinzipiell alle geeignet für den Einsatz in der Qualitätssicherung der dynamischen Zellkultur. Ein kombiniertes Untersuchungsschema bestehend aus Parametern die die Integrität der Zellmembranen reflektieren, wie die Freisetzung von Enzymen, sowie metabolischen Parametern wie Lidocain, Galaktose, Sorbitol als auch Syntheseparameter, für Proteine Albumin, als Hepatozyten typische Leistungen die Synthese von Harnstoff und der Abbau von Lactat ist in der Lage einen ausreichend umfassenden Einblick in den Status der dynamischen Zellkultur zu liefern. / Objectives of this work were to find easy to handle every day quality assessment procedure for bioreactors that are intended for clinical trials, further more usefulness of these parameters in characterization and standardization of the Liver Support System. Parameters for evaluation had been: Lidocaine, Megx, Sorbitol, Galactose, Urea, Albumin and Lactate. Bolus and Continuous metabolic liver functions tests had been done, for synthesis and detoxification parameters liberation was measured by concentration. Highly significant difference between bioreactor with primary porcine liver cells and cell-free devices was shown by t-tests. Differences to other groups like infected bioreactors had been demonstrated with ANOVA. Results show typical course over the culture period that can be categorized into a initial phase of cell reorganization, a stable culture phase and an extended phase with slow decay. All parameter proved to be suitable for daily routine quality assessment in dynamic cell culture systems. The combination of parameters reflecting different specific cellular function is able to give more comprehensive insights in the status of the cell culture.