Farmacocinética pré-clínica do praziquantel carreado por micropartículas inorgânicas
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Data
2021-12-16
Autores
Vivêncio, Eduardo Henrique
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
O praziquantel (PZQ) é fármaco de escolha no tratamento da esquistossomose, porém, sua baixa solubilidade em água pode ser um problema nas administrações orais. O PZQ, ainda, sofre extenso metabolismo pré-sistêmico, o que leva à expectativa de que os níveis plasmáticos atingidos na administração oral apresentem alta variabilidade, com reflexos significativos sobre o desfecho clínico. Formulações com hidróxidos duplos lamelares (HDL) como excipientes funcionais em micropartículas inorgânicas têm sido desenvolvidas com a finalidade de melhorar o perfil de dissolução e a biodisponibilidade oral de fármacos. Neste estudo, o objetivo foi avaliar o impacto de uma nova formulação desenvolvida como sistema PZQ-HDL, pelo Laboratório de Tecnologia de Medicamentos da Universidade Federal de Pernambco (UFPE), sobre o perfil farmacocinético do PZQ em ratos wistar. Foi desenvolvido e validado um método bioanalítico para a determinação de PZQ em plasma de ratos por HPLC/UV. O fármaco foi administrado em quatro grupos de animais: por via intravenosa (IFA, 20 mg/kg) e por via oral (IFA dispersão sem adjuvantes funcionais, suspensão oral comercial - SO e PZQ carreado por HDL; 200 mg/kg), com coleta seriada de sangue para a quantificação do PZQ no período de até 360 e 480 minutos, respectivamente. Não foram observados niveis quantificáveis de PZQ no grupo de que recebeu IFA dispersão pela via oral. Os parâmetros farmacocinéticos principais estimados para o grupo IV, PZQ-HDL e Suspensão comercial foram: Kel (min-1) – 0,038, 0,006 e 0,005; t 1/2 (min) – 18,2, 115,50 e 136,6; ASC0-t (ug/mL.min) – 329,99, 1278,50 e 522,7; ASC0-inf (ug/mL.min) – 379,6, 1346,74 e 585,4; Cl (mL/min/Kg) – 12,64, 52,69 e 52,7; Vd (mL/Kg) – 332,78, 8780,94 e 10537,1; MRT (min) – 28, 153,07 e 196,7. Observou-se que, a partir dos 10 minutos iniciais, o grupo que recebeu a formulação HDL apresentou concentrações plasmáticas de PZQ sempre superiores, demonstrando que o processo de absorção foi incrementado quando comparado com a administração da formulação SO. A biodisponibilidade oral (F%) foi de 36,2 e 16,1 para HDL e SO, respectivamente. Este resultado nos permite inferir que as partículas inorgânicas aumentaram a quantidade de fármaco absorvida, o que representa êxito na proposta da formulação. Ensaios com outros modelos animais devem ser realizados para o avanço do desenvolvimento do produto farmacêutico com perspectivas promissoras.
Praziquantel (PZQ) is the drug of choice in the treatment of schistosomiasis, however, its low water solubility can be limiting for its oral administration. PZQ also undergoes extensive pre-systemic metabolism, which leads to the expectation that the plasma levels reached after oral administration will show high variability, with significant effects on the clinical outcome. Formulationswith lamellar double hydroxides (HDL) as functional excipients in inorganic microparticles have been developed with the aim of improving the dissolution profile and oral bioavailability of drugs. In this study, the objective was toevaluate the impact of a new formulation developed as a PZQ-HDL system, developed by the Medicinal Technology Laboratory of the Federal University of Pernambco (UFPE), on the pharmacokinetic profile of PZQ in Wistar rats. A bioanalytical method for the determination of PZQ in rat plasma was developed and validated by HPLC/UV. The drug was administered in four groups of animals: intravenously (IFA, 20 mg/kg) and orally (IFA suspension without functional adjuvants, commercial oral suspension - SO and PZQ carried by HDL; 200 mg/kg), with serial blood collection for PZQ quantification within 360 and 480 minutes, respectively. No quantifiable levels of PZQ were observed in the group that received IFA suspension orally. The main pharmacokinetic parameters estimated for group IV, PZQ-HDL and commercial suspension were: Kel (min-1) – 0.038, 0.006 and 0.005; t 1/2 (min) - 18.2, 115.50 and 136.6; AUC0-t (ug/ml.min) - 329.99, 1278.50 and 522.7; AUC0-inf (ug/ml.min) - 379.6, 1346.74 and 585.4; Cl (mL/min/Kg) - 12.64, 52.69 and 52.7; Vd (mL/Kg) - 332.78, 8780.94 and 10537.1; MRT (min) - 28, 153.07 and 196.7. It was observed that, during the initial 10 minutes, the group that received the HDL formulation had always higher plasma concentrations of PZQ, demonstrating that the absorption process was increased when compared to the administrationof the SO formulation. The oral bioavailability (%F) was 36.2 and 16.1 for HDL and SO, respectively. This result allows us to infer that the inorganic particles increased the amount of drug absorbed, which represents the success of the formulation proposed. Assays with other animal models should be carried out toadvance the development of the pharmaceutical product with promising perspectives.
Praziquantel (PZQ) is the drug of choice in the treatment of schistosomiasis, however, its low water solubility can be limiting for its oral administration. PZQ also undergoes extensive pre-systemic metabolism, which leads to the expectation that the plasma levels reached after oral administration will show high variability, with significant effects on the clinical outcome. Formulationswith lamellar double hydroxides (HDL) as functional excipients in inorganic microparticles have been developed with the aim of improving the dissolution profile and oral bioavailability of drugs. In this study, the objective was toevaluate the impact of a new formulation developed as a PZQ-HDL system, developed by the Medicinal Technology Laboratory of the Federal University of Pernambco (UFPE), on the pharmacokinetic profile of PZQ in Wistar rats. A bioanalytical method for the determination of PZQ in rat plasma was developed and validated by HPLC/UV. The drug was administered in four groups of animals: intravenously (IFA, 20 mg/kg) and orally (IFA suspension without functional adjuvants, commercial oral suspension - SO and PZQ carried by HDL; 200 mg/kg), with serial blood collection for PZQ quantification within 360 and 480 minutes, respectively. No quantifiable levels of PZQ were observed in the group that received IFA suspension orally. The main pharmacokinetic parameters estimated for group IV, PZQ-HDL and commercial suspension were: Kel (min-1) – 0.038, 0.006 and 0.005; t 1/2 (min) - 18.2, 115.50 and 136.6; AUC0-t (ug/ml.min) - 329.99, 1278.50 and 522.7; AUC0-inf (ug/ml.min) - 379.6, 1346.74 and 585.4; Cl (mL/min/Kg) - 12.64, 52.69 and 52.7; Vd (mL/Kg) - 332.78, 8780.94 and 10537.1; MRT (min) - 28, 153.07 and 196.7. It was observed that, during the initial 10 minutes, the group that received the HDL formulation had always higher plasma concentrations of PZQ, demonstrating that the absorption process was increased when compared to the administrationof the SO formulation. The oral bioavailability (%F) was 36.2 and 16.1 for HDL and SO, respectively. This result allows us to infer that the inorganic particles increased the amount of drug absorbed, which represents the success of the formulation proposed. Assays with other animal models should be carried out toadvance the development of the pharmaceutical product with promising perspectives.
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Palavras-chave
praziquantel, farmacocinética, hidróxidos duplo lamelares, HPLC, double lamellar hydroxides