Impacto dos polimorfismos genéticos de OCT2 e OCTN1 na disposição cinética da gabapentina em pacientes com dor crônica
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Data
2018-06-15
Autores
Yamamoto, Priscila Akemi
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A gabapentina (GAB) é um anticonvulsivante indicado para o tratamento de epilepsia e dor crônica. Possui cinética não linear relacionada a saturação do processo de absorção, não é metabolizada e é eliminada principalmente por excreção renal. Estudos sugerem a atividade dos transportadores de cátions orgânicos (OCT2 e OCTN1) na secreção renal da GAB. O objetivo do estudo foi investigar a influência dos polimorfismos genéticos de OCT2 e OCTN1 e outras possíveis covariáveis na disposição cinética da GAB em pacientes tratados com doses múltiplas. Os métodos de cromatografia líquida de alta eficiência com detecção por ultravioleta (CLAE-UV) para determinação da concentração de GAB no plasma e na urina foram desenvolvidos e validados segundo a RDC nº 27/2012 da ANVISA. Foi utilizado como agente derivatizante o 1-flúor-2,4-dinitrobenzeno, e como padrão interno o anlodipino. Os métodos apresentaram linearidade na faixa de 200-14.000 ng/mL de plasma e 2-120 µg/mL de urina. Foram investigados 66 participantes (35 mulheres e 31 homens), com idade média de 54 anos e com dor crônica tratados com GAB por pelo menos 7 dias. Os participantes foram genotipados como GG (n=58) e GT (n=8) para o polimorfismo SLC22A2 c.808G>T e CC (n=31), CT (n= 27) e TT (n=8) para o polimorfismo SLC22A4 c.1507C>T. As concentrações plasmáticas mínima de GAB no estado de equilíbrio variaram de 402,0 a 11.937,9 ng/mL durante tratamento com doses diárias que variaram de 600 a 3.600 mg. A idade e a taxa de filtração glomerular estimada apresentaram correlação significativa com a razão concentração plasmática mínima de GAB/dose diária. Outras variáveis (sexo, peso corporal e índice de massa corporal) não apresentaram correlação. A taxa de filtração glomerular estimada e a dose diária foram as covariáveis relevantes para predizer a concentração plasmática mínima de GAB no estado de equilíbrio, explicando 68% da variabilidade na concentração plasmática. A análise populacional indicou que apenas a taxa de filtração glomerular possui efeito sob o clearance de GAB. Os polimorfismos SLC22A2 c.808G>T e SLC22A4 c.1507C>T não apresentaram influência na razão concentração plasmática mínima da GAB/dose diária e nos parâmetros farmacocinéticos populacionais estimados (constante de absorção, volume de distribuição e clearance). Em conclusão, a farmacocinética clínica da GAB é fortemente influenciada pela função renal e pela saturação dos processos de absorção e não pela farmacogenética de OCT2 e OCTN1.
Gabapentin (GAB) is an anticonvulsant indicated for the treatment of epilepsy and chronic pain. It has nonlinear kinetics due to the saturation of absorption process, is not metabolized and is mainly eliminated by renal excretion. Studies suggest the activity of organic cation transporters (OCT2 and OCTN1) in the renal excretion of GAB. The aim of this study is to investigate the influence of genetic polymorphisms of OCT2 and OCTN1 and other possible covariates on the kinetic disposition of GAB in patients treated with multiple doses. High performance liquid chromatography with ultraviolet detection (HPLC-UV) methods for the determination of GAB plasma and urine concentration were developed and validated according to RDC nº 27/2012 of ANVISA. 1-fluoro-2,4-dinitrobenzene was used as derivatization agent, and amlodipine as internal standard. The methods showed linearity in the range of 200-14,000 ng/mL of plasma and 2-120 µg/mL of urine. Sixty-six participants (35 women and 31 men), with mean age of 54 years and with chronic pain treated with GAB for at least 7 days were investigated. They were genotyped as GG (n=58) and GT (n=8) for SLC22A2 c.808G>T polymorphism and as CC (n=31), CT (n=27) and TT (n=8) for SLC22A4 c.1507C>T polymorphism. GAB steady-state minimum plasma concentrations ranged from 402.0 to 11,937.9 ng/mL during the treatment with daily doses ranging from 600 to 3,600 mg. Age and estimated glomerular filtrate rate showed significant correlation with the plasma concentration of GAB/daily dose ratio. Other variables (gender, body weight and body mass index) were not correlated. The estimated glomerular filtration rate and daily dose were found as significant covariates to predict GAB minimum plasma concentration at steady-state, explained 68% of plasma concentration variability. The population pharmacokinetics showed that GAB clearance was affected only by the glomerular filtration ratio. SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms did not influence the GAB minimum plasma concentration/daily dose ratio and the estimated population pharmacokinetic parameters (first-order absorption rate constant, volume of distribution and clearance). In conclusion, gabapentin clinical pharmacokinetics is strongly influenced by renal function and the absorption process saturation and not by the pharmacogenetics of OCT2 and OCTN1.
Gabapentin (GAB) is an anticonvulsant indicated for the treatment of epilepsy and chronic pain. It has nonlinear kinetics due to the saturation of absorption process, is not metabolized and is mainly eliminated by renal excretion. Studies suggest the activity of organic cation transporters (OCT2 and OCTN1) in the renal excretion of GAB. The aim of this study is to investigate the influence of genetic polymorphisms of OCT2 and OCTN1 and other possible covariates on the kinetic disposition of GAB in patients treated with multiple doses. High performance liquid chromatography with ultraviolet detection (HPLC-UV) methods for the determination of GAB plasma and urine concentration were developed and validated according to RDC nº 27/2012 of ANVISA. 1-fluoro-2,4-dinitrobenzene was used as derivatization agent, and amlodipine as internal standard. The methods showed linearity in the range of 200-14,000 ng/mL of plasma and 2-120 µg/mL of urine. Sixty-six participants (35 women and 31 men), with mean age of 54 years and with chronic pain treated with GAB for at least 7 days were investigated. They were genotyped as GG (n=58) and GT (n=8) for SLC22A2 c.808G>T polymorphism and as CC (n=31), CT (n=27) and TT (n=8) for SLC22A4 c.1507C>T polymorphism. GAB steady-state minimum plasma concentrations ranged from 402.0 to 11,937.9 ng/mL during the treatment with daily doses ranging from 600 to 3,600 mg. Age and estimated glomerular filtrate rate showed significant correlation with the plasma concentration of GAB/daily dose ratio. Other variables (gender, body weight and body mass index) were not correlated. The estimated glomerular filtration rate and daily dose were found as significant covariates to predict GAB minimum plasma concentration at steady-state, explained 68% of plasma concentration variability. The population pharmacokinetics showed that GAB clearance was affected only by the glomerular filtration ratio. SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms did not influence the GAB minimum plasma concentration/daily dose ratio and the estimated population pharmacokinetic parameters (first-order absorption rate constant, volume of distribution and clearance). In conclusion, gabapentin clinical pharmacokinetics is strongly influenced by renal function and the absorption process saturation and not by the pharmacogenetics of OCT2 and OCTN1.
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Palavras-chave
gabapentina, farmacogenética, transportadores de fármacos, polimorfismo de nucleotídeo único, SLC22A2, SLC22A4, gabapentin, pharmacogenetics, drug carriers, single nucleotide polymorphism