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Thèse de Doctorat
DOI
https://doi.org/10.11606/T.9.2004.tde-10112021-180034
Document
Auteur
Nom complet
Ismar Rodrigues
Unité de l'USP
Domain de Connaissance
Date de Soutenance
Editeur
São Paulo, 2004
Directeur
Titre en portugais
Interação de antagonistas H2 no metabolismo enantiosseletivo do albendazol em pacientes com neurocisticercose. Cafeína como fármaco marcador do CYP1A2
Resumé en portugais
O estudo investiga a associação da ranitidina ou da cimetidina no metabolismo enantiosseletivo do albendazol, administrado em regime de dose múltipla (7,5 mg/Kg/12 h) a pacientes (n = 27) portadores da forma ativa da neurocisticercose intraparenquimatosa. Os pacientes foram divididos em 3 grupos, de acordo com a medicação associada (controle, cimetidina 800 mg/dia ou ranitidina 300 mg/dia). No 8° dia de tratamento com o albendazol, os pacientes receberam 100 mg de cafeína como fármaco marcador do CYP1A2, sendo colhidas amostras seriadas de sangue (0-24 h), uma amostra de líquido cefalorraquidiano (LCR, 0-12 h) e amostras de urina (0-8, 8-16, 16-24 h). Os metabólitos do albendazol no plasma e no LCR foram analisados por HPLC, em coluna de fase quiral e detecção por fluorescência. A cafeína e seus metabólitos foram quantificados por HPLC, em coluna RP Select B e detecção por ultravioleta. As seguintes diferenças (p ≤ 0,05) foram observadas para o (+)-sulfóxido de albendazol (mediana), respectivamente, nos grupos controle e cimetidina: Cmax 255,0 vs 562,9 ng/mL, AUCSS 0-12 1,80 vs 4,87 µg.h/mL e C1/fm 2,32 vs 0,98 L/h.Kg. Considerando que os parâmetros farmacocinéticos do (-)-sulfóxido de albendazol não foram alterados, os dados sugerem que a cimetidina inibe de maneira enantiosseletiva a sulfonação do (+)-sulfóxido de albendazol. A ranitidina não alterou o metabolismo enantiosseletivo do albendazol. A inibição do CYP1A2 no grupo ranitidina foi demonstrada pela redução (p ≤ 0,05) do clearance total da cafeína (controle 0,15 vs cimetidina 0,10 vs ranitidina 0,15 mL/min.Kg) e das razões metabólicas em plasma (controle 1,0 vs cimetidina 0,48 vs ranitidina 0,84) e urina (controle 7,10 vs cimetidina 3,16 vs ranitidina 5,51). Os coeficientes de correlação (p ≤ 0,05) obtidos entre os clearances de formação do (+)-sulfóxido de albendazol e (-)-sulfóxido de albendazol e as razões metabólicas da cafeína em plasma e urina indicam o envolvimento do CYP1A2 na sulfonação do sulfóxido de albendazol. Concluindo, a associação de ranitidina ou cimetidina com o albendazol resulta em concentrações plasmáticas e no LCR de ambos os enantiômeros do sulfóxido de albendazol compatíveis com a eficácia do albendazol no tratamento da neurocisticercose.
Titre en anglais
Interação de antagonistas H2 no metabolismo enantiosseletivo do albendazol em pacientes com neurocisticercose. Cafeína como fármaco marcador do CYP1A2
Resumé en anglais
The association of ranitidine or cimetidine in the enantioselective metabolism of albendazole was studied after administration in a multiple dose regimen (7.5 mg/kg/12 h) to patients (n = 27) with the active form of intraparenchymatous neurocysticercosis. The patients were divided into 3 groups according to the associated medication (control, cimetidine 800 mg/day or ranitidine 300 mg/day). On the 8th day of albendazole treatment, the patients received 100 mg caffeine as a CYP1A2 marker drug and were submitted to collection of serial blood samples (0.24 h), one sample of cerebrospinal fluid (CSF, 0-12 h), and urine samples (0-8, 8-16, 16-24 h). The albendazole metabolites in plasma and CSF were analyzed by HPLC on a chiral phase column and by fluorescence detection. Caffeine and its metabolites were quantified by HPLC on an RP Select B column and by ultraviolet detection. The following differences (p ≤ 0.05) were observed for (+)-albendazole sulfóxide (median) between the control and cimetidine group, respectively: Cmax 255.0 vs 562.9 ng/ml, AUCSS 0-12 1.80 vs 4.87 µg.h/mL and Cl/fm 2,32 vs 0.98 L/h.kg. Since the pharmacokinetic parameters of (-)-albendazole sulfoxide were unchanged, the data suggest that cimetidine inhibits the sulfonation of (+)albendazole sulfoxide in an enantioselective manner. Ranitidine did not alter the enantioselective metabolism of albendazole. The inhibition of CYP1A2 in the ranitidine group was demonstrated by the reduction (p ≤ 0.05) of total caffeine clearance (contral 0.15 vs cimetidine 0.10 vs ranitidine 0.15 mL/min.kg) and of the metabolic ratios in plasma (control 1.0 vs cimetidine 0.48 vs ranitidine 0.84) and urine (control 7.10 vs cimetidine 3.16 vs ranitidine 5.51). The correlation coefficients (p ≤ 0.05) obtained between the clearance of formation of (+)albendazole sulfoxide and (-)-albendazole sulfoxide and the metabolic ratios of caffeine in plasma and urine suggest the involvement of CYP1A2 in the sulfonation of albendazole sulfoxide. ln conclusion, the combination of ranitidine or cimetidine with albendazole results in plasma and CSF concentrations of the two enantiomers of albendazole sulfoxide that are compatible with the efficacy of albendazole in the treatment of neurocysticercosis.
 
Date de Publication
2021-11-10
 
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