O trans-tramadol (trans-T), é um analgésico de ação central disponível na clínica como mistura racêmica dos enantiômeros (+)-trans-T e (-)-trans-T. O trans-T é biotransformado pelo CYP2D ao metabólito ativo O-desmetiltramadol (M1) e pelo CYP2B e CYP3A ao metabólito inativo N-desmetiltramadol (M2). O estudo investiga a influência do diabetes experimental na disposição cinética e no metabolismo dos enantiômeros do trans-T e seus metabólitos em animais tratados ou não com insulina e/ou quinidina. Os ratos machos Wistar foram divididos nos grupos controle, quinidina (dose única de quinidina i.p. 80mg/Kg 4 h antes do trans-T), diabético (dose única de estreptozotocina i.v. 45 mg/kg), diabético insulina (insulina NPH 2 UI/dia durante 12 dias), diabético quinidina e diabético insulina quinidina. Os animais (n=6/tempo de coleta) receberam dose única oral (gavagem) de 20 mg/kg de rac-trans-T e as coletas seriadas de sangue foram realizadas até 12 h após a administração. As concentrações plasmáticas dos enantiômeros do trans-T, M1 and M2 foram determinadas por LC-MS-MS usando a coluna de fase quiral Chiralpak® AD. Os parâmetros farmacocinéticos foram calculados com auxílio do programa WinNonlin 4.1. e expressos como mediana. A disposição cinética do trans-T é enantiosseletiva no grupo controle com acúmulo plasmático do (+)-trans-T (AUC 527,88 vs 116,38 ng.h/mL) e do (+)-M2 (AUC 1210,90 vs 225,34 ng.h/mL); teste de Wilcoxon com p<0,05. A administração de quinidina mostra perda da enantiosseletividade na disposição cinética do trans-T e acúmulo plasmático do (-)-M1 (AUC 957,61 vs 1672,70 ng.h/mL) e do (+)-M2 (AUC 4732,40 vs 1582,80 ng.h/mL). A comparação entre os grupos controle e quinidina permite observar que o tratamento com quinidina resulta em acúmulo plasmático do (-)-trans-T (AUC 828,44 vs 116,38 ng.h/mL), (+)-trans-T (AUC 2243,10 vs 527,88 ng.h/mL), (-)-M2 (AUC 1582,80 vs 225,34 ng.h/mL) e (+)-M2 (AUC 4732,40 vs 1210,90 ng.h/mL). Os animais com diabetes induzido por estreptozotocina quando comparados ao grupo controle mostram inibição (teste Kruskall-Wallis, p<0,05) do metabolismo do (+)-trans-T (AUC 527,88 vs 2617,80 ng.h/mL), (-)-trans-T (AUC 116,38 vs 1081,70 ng.h/mL) e do (-)-M1 (918,52 vs 2723,90 ng.h/mL). O tratamento com insulina durante 12 dias reverte a inibição preferencial no metabolismo do (-)-trans-T causada pelo diabetes experimental. Os valores de AUC do (-)-trans-T no grupo diabetes insulina (195,42 ng.h/mL) são próximos aos valores reportados para o grupo controle (116,38 ng.h/mL) e menores do que aqueles reportados para o grupo diabético (1081,70 ng.h/mL). Em relação ao (+)-trans-T pode-se observar tendência de redução nas concentrações plasmáticas no grupo de animais diabéticos tratados com insulina (AUC 1460,10 ng.h/mL) em relação ao grupo diabético (AUC 2617,80 ng.h/mL). Concluindo, os animais com diabetes induzido por estreptozotocina mostram inibição preferencial do metabolismo do (-)-trans-T, a qual é revertida pelo tratamento com insulina durante 12 dias. O tratamento com quinidina resulta em acúmulo plasmático do (-)-trans-T, (+)-trans-T, (-)-M2 e (+)-M2. Ressalta-se, no entanto que nos animais com diabetes induzido por estreptozotocina tratados ou não com insulina a quinidina não altera a disposição cinética de ambos os enantiômeros do trans-T. / Trans-tramadol (trans-T) is a central action analgesic, which is available in clinical practice as a racemic mixture of the (+)-trans-T and (-)-trans-T enantiomers. Trans-T is biotransformed by CYP2D to the active metabolite O-desmethyltramadol (M1) and by CYP2B and CYP3A to the inactive metabolite N-desmethyltramadol (M2). This study investigates the influence of experimental diabetes on the kinetic disposition and metabolism of the enantiomers of trans-T and its metabolites in animals treated or not with insulin and/or quinidine. Male Wistar rats were divided into the following groups: control, quinidine (single i.p. dose of 80 mg/kg quinidine administered 4 h before trans-T), diabetic (single i.v. dose of 45 mg/kg streptozotocin), insulin diabetic (2 IU/day NPH insulin for 12 days), quinidine diabetic, and insulin+quinidine diabetic. The animals (n=6 per sampling time) received a single oral (gavage) dose of 20 mg/kg racemic trans-T and serial blood samples were collected up to 12 h after administration of the drug. Plasma concentrations of the trans-T, M1 and M2 enantiomers were determined by LC-MS/MS using a Chiralpak® AD chiral column. The pharmacokinetic parameters were calculated using the WinNonlin 4.1 program and are expressed as median. The kinetic disposition of trans-T was enantioselective in the control group, with the plasma accumulation of (+)-trans-T (AUC 527.88 vs 116.38 ng.h/mL) and (+)-M2 (AUC 1210.90 vs 225.34 ng.h/mL) (Wilcoxon test, p<0.05). The administration of quinidine resulted in the loss of enantioselectivity in the kinetic disposition of trans-T and in the plasma accumulation of (-)-M1 (AUC 957.61 vs 1672.70 ng.h/mL) and (+)-M2 (AUC 4732.40 vs 1582.80 ng.h/mL). Comparison between the control and quinidine groups showed that treatment with quinidine resulted in the plasma accumulation of (-)-trans-T (AUC 828.44 vs 116.38 ng.h/mL), (+)-trans-T (AUC 2243.10 vs 527.88 ng.h/mL), (-)-M2 (AUC 1582.80 vs 225.34 ng.h/mL), and (+)-M2 (AUC 4732.40 vs 1210.90 ng.h/mL). Inhibition of the metabolism of (+)-trans-T (AUC 527.88 vs 2617.80 ng.h/mL), (-)-trans-T (AUC 116.38 vs 1081.70 ng.h/mL), and (-)-M1 (918.52 vs 2723.90 ng.h/mL) was observed in animals with streptozotocin-induced diabetes when compared to the control group (Kruskal-Wallis test, p<0.05). Treatment with insulin for 12 days reversed the preferential inhibition of the metabolism of (-)-trans-T caused by experimental diabetes. The AUC value of (-)-trans-T obtained for the insulin diabetic group (195.42 ng.h/mL) was close to that found for the control group (116.38 ng.h/mL) and lower than that observed for the diabetic group (1081.70 ng.h/mL). Plasma concentrations of (+)-trans-T tended to be lower in the group of diabetic animals treated with insulin (AUC 1460.10 ng.h/mL) compared to the diabetic group (AUC 2617.80 ng.h/mL). In conclusion, preferential inhibition of the metabolism of (-)-trans-T is observed in animals with streptozotocin-induced diabetes, which is reversed by insulin treatment for 12 days. Treatment with quinidine results in the plasma accumulation of (-)-trans-T, (+)-trans-T, (-)-M2, and (+)-M2. However, quinidine does not alter the kinetic disposition of either trans-T enantiomer in animals with streptozotocin-induced diabetes treated or not with insulin.
| Identifer | oai:union.ndltd.org:IBICT/oai:teses.usp.br:tde-06042010-142819 |
| Date | 21 October 2009 |
| Creators | Ana Leonor Pardo Campos Godoy |
| Contributors | Vera Lucia Lanchote, Pierina Sueli Bonato, Jose Salvador Lepera, Rosangela Gonçalves Peccinini, Cristina Helena dos Reis Serra |
| Publisher | Universidade de São Paulo, Toxicologia, USP, BR |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | Portuguese |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da USP, instname:Universidade de São Paulo, instacron:USP |
| Rights | info:eu-repo/semantics/openAccess |
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