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Doctoral Thesis
DOI
https://doi.org/10.11606/T.60.2020.tde-18122019-162845
Document
Author
Full name
Ana Carolina Conchon Costa
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2019
Supervisor
Committee
Moraes, Natalia Valadares de (President)
Marques, Vanessa Bergamin Boralli
Cunha, Thiago Mattar
Garcia, Luis Vicente
Tirapelli, Carlos Renato
Title in Portuguese
Disposição cinética e excreção renal da gabapentina: o papel dos transportadores para cátions orgânicos e o efeito do controle glicêmico em pacientes com dor neuropática
Keywords in Portuguese
CTZ
Diabetes tipo 2
Dor neuropática
Farmacocinética
GBP
OCT2
Abstract in Portuguese
A gabapentina (GBP), anticonvulsivante utilizado para tratamento de dor neuropática, é eliminada principalmente inalterada na urina. Estudos sugerem que a secreção tubular ativa nos rins contribui para a excreção de GBP. Estudos em ratos com diabetes experimental sugerem que a hiperglicemia reduz a atividade de transportadores de cátions orgânicos (Octs). Assim, o objetivo deste estudo foi investigar o papel dos OCTs na disposição cinética e na farmacodinâmica da GBP em pacientes com dor neuropática e verificar a regulação da atividade desses transportadores pelo controle glicêmico no diabetes. Foi realizado estudo in vitro para avaliar a interação de GBP e do provável inibidor de OCTs cetirizina (CTZ) com transportadores OCT1, OCT2, OCT3, OCTN1, MATE1 e MATE2-K expressos em células HEK. O estudo clínico cruzado foi realizado em pacientes com dor neuropática (n=10, Controle) para avaliar a influência da CTZ na disposição cinética da GBP. Para avaliar o efeito do controle glicêmico, foram investigados pacientes com DM2 controlado (DC, n=9) e DM2 não controlado (DNC, n=10). Todos os participantes investigados apresentavam dor neuropática de intensidade >= 4 na escala visual analógica de dor (EVA) e foram tratados com dose única oral de 300 mg de GBP (Fase 1) ou CTZ (20 mg/dia) durante 5 dias e dose única de GBP no último dia (Fase 2). Apenas os pacientes do grupo Controle participaram da Fase 2. Amostras seriadas de sangue e urina foram coletadas até 36 horas após a administração de GBP. A intensidade de dor foi avaliada nos mesmos tempos de coleta de sangue. Todos os participantes foram genotipados para os polimorfismos SLC22A2 808G>T e SLC22A4 1507C>T. Os parâmetros farmacocinéticos foram estimados por análise não-compartimental. Os experimentos in vitro mostraram que a GBP é substrato para hMATE1 e hOCTN1, e que sua interação com hOCT2 não é clinicamente relevante. A CTZ inibiu os transportadores hOCTs e hMATEs. No estudo clínico, a coadministração de CTZ resultou em aumento de CL/F (14,6 L/h) e Vd/F (151,9 L) e redução de AUC0-? (20,6 ?g.h/mL), quando comparados com a administração da GBP apenas (CL/F: 10,6 L/h; Vd/F 106,2 L; AUC0-? 28,2 ?g.h/mL). As menores concentrações plasmáticas de GBP quando coadministrada com CTZ resultaram em redução na atenuação de dor. O grupo DNC apresentou diferenças marginais nos parâmetros Cmax (1,86 ?g/mL, p=0,08780) e Vd/F (178,8 L, p=0,0506), em relação ao grupo Controle (Cmax: 2,48 ?g/mL; Vd/F: 106,2 L). Não foi encontrada diferença na disposição cinética da GBP entre os genótipos para os polimorfismos investigados. Conclusão: a GBP é substrato dos transportadores renais hMATE1, hOCTN1 e hOCT2. O tratamento com CTZ e a hiperglicemia reduziram a exposição sistêmica da GBP, contudo essas alterações não podem ser explicadas por interação com os transportadores renais. Estes dados sugerem que a CTZ e a hiperglicemia reduzem a biodisponibilidade oral da GBP por saturação dos processos de absorção intestinal
Title in English
Gabapentin kinetic disposition and renal excretion: role of transporters for organic cations and the effect of glycemic control in patients with neuropathic pain
Keywords in English
CTZ
GBP
Neuropathic pain
OCT2
Pharmacokinetics
Type-2 diabetes
Abstract in English
Gabapentin (GBP), anticonvulsant used to neuropathic pain treatment, is mainly eliminated unchanged in urine. Renal active tubular secretion has been suggested to contribute on GBP excretion by renal excretion. Studies performed on rats with experimental diabetes suggest that hyperglycemia reduces the activity of organic cation transporters (Oct). Thus, the aim of the study was to investigate the role of OCTs on kinetic disposition and pharmacodynamics of GBP in patients with neuropathic pain and to verify the regulation of these transporters' activity by glycemic control in diabetes. An in vitro study was performed to evaluate the interaction of GBP and the probable OCTs inhibitor cetirizine (CTZ) with transporters OCT1, OCT2, OCT3, OCTN1, MATE1 and MATE2-K expressed in HEK cells. A cross-over clinical study was performed in patients with neuropathic pain (n=10, Control) to evaluate the influence of CTZ on GBP kinetic disposition. To evaluate the effect of glycemic control, patients with controlled DM2 (DC, n=9) and uncontrolled DM2 (DNC, n=10) were investigated. All participants investigated had neuropathic pain of intensity >= 4 evaluated by analogue visual scale (EVA) and were treated with oral single-dose of 300 mg of GBP (Phase 1) or cetirizine (20 mg/day) for 5 days and single-dose of GBP on the last day (Phase 2). Only participants of Control group participated of Phase 2. Serial blood and urine samples were collected up to 36 hours after GBP administration. Pain intensity was evaluated on the same time of blood samples. All participants were genotyped for polymorphisms SLC22A2 808G>T and SLC22A4 1507C>T. The pharmacokinetic parameters were estimated by non-compartmental analysis. The in vitro experiments showed that GBP is a substrate for hMATE and hOCTN1, and that the interaction with hOCT2 is not clinically relevant. CTZ inhibits the transporters hOCTs and hMATEs. In the clinical study, the coadministration of CTZ resulted in increase of CL/F (14.6 L) and Vd/F (151.9 L) and decrease of AUC0-? (20.6 ?g.h/mL) when compared to the administration of GBP alone (CL/F: 10.6 L/h); Vd/F: 106.2 L; AUC0-?: 28.2 ?g.h/mL). The lower plasma concentrations of GBP when coadministered with CTZ resulted in reduced pain attenuation. The DNC group showed marginal differences in parameters Cmax (1.86 ?g/mL, p=0.08780) and Vd/F (178.8 L, p=0.0506) in relation to Control group (Cmax: 2.48 ?g/mL; Vd/F: 106.2 L). No differences were found on GBP kinetic disposition between genotypes for investigated polymorphisms. Conclusion: GBP is a substrate for renal transporters hMATE, hOCTN1 and hOCT2. The treatment with CTZ and hyperglycemia reduced systemic exposure to GBP, although these changes cannot be explained by the interaction with renal transporters. These data suggest that CTZ and hyperglycemia reduce GBP oral bioavailability by saturation of intestinal absorption processes
 
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Release Date
2021-12-17
Publishing Date
2020-02-28
 
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