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1.
J Chromatogr Sci ; 57(10): 874-880, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31602469

RESUMO

A simple and rapid ultra-high-performance liquid chromatography (UHPLC) method for determination of efavirenz (EFV) in plasma was developed and applied in a preclinical pharmacokinetic study. The method involves only addition of acetonitrile to precipitation of plasma proteins followed by solvent evaporation. The mobile phase consisted of methanol, acetonitrile and 0.1 M formic acid (20:50:30) at a flow rate of 0.3 mL/min with run time of 5 min. A CSH C18 column and a UHPLC-UV system operating at 245 nm were used. There was a linear response in the range of 0.078 to 10 µg/mL, and the equation was obtained by weighting (1/x2) with r2 = 0.9965. The pharmacokinetic disposition of EFV was investigated in rabbits (two groups, n = 7) following a single intravenous administration (IV group) at a dose of 2.7 mg/kg and a single oral administration (oral group) of EFV co-administered with lamivudine (3TC) and tenofovir (TNF) at a dose of 50, 25 and 25 mg, respectively. The study demonstrated the applicability of the method for determination of EFV in plasma without interference from other co-administered drugs, and the pharmacokinetic parameters were calculated. The method showed advantages over other methods in the literature, such as simplicity of sample processing and fast results.


Assuntos
Benzoxazinas/sangue , Benzoxazinas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Alcinos , Animais , Benzoxazinas/química , Ciclopropanos , Avaliação Pré-Clínica de Medicamentos , Limite de Detecção , Modelos Lineares , Coelhos , Reprodutibilidade dos Testes
2.
Drug Metab Dispos ; 46(6): 879-887, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29618574

RESUMO

Thiazolidinediones (TZDs) are drugs used to treat type 2 diabetes mellitus; however, several safety concerns remain regarding the available drugs in this class. Therefore, the search for new TZD candidates is ongoing; metabolism studies play a crucial step in the development of new candidates. Pioglitazone, one of the most commonly used TZDs, and GQ-11, a new N-substituted TZD, were investigated in terms of their metabolic activity in rat and human liver microsomes to assess their metabolic stability and investigate their metabolites. Methods for preparation of samples were based on liquid-liquid extraction and protein precipitation. Quantitation was performed using liquid chromatography (LC)-tandem mass spectrometry, and the metabolite investigation was performed using ultraperformance LC coupled to a hybrid quadrupole-time of flight mass spectrometer. The predicted intrinsic clearance of GQ-11 was 70.3 and 46.1 ml/kg per minute for rats and humans, respectively. The predicted intrinsic clearance of pioglitazone was 24.1 and 15.9 ml/kg per minute for rats and humans, respectively. The pioglitazone metabolite investigation revealed two unpublished metabolites (M-D and M-A). M-A is a hydration product and may be related to the mechanism of ring opening and the toxicity of pioglitazone. The metabolites of GQ-11 are products of oxidation; no ring-opening metabolite was observed for GQ-11. In conclusion, under the same experimental conditions, a ring-opening metabolite was observed only for pioglitazone. The resistance of GQ-11 to the ring opening is probably related to N-substitution in the TZD ring.


Assuntos
Tiazolidinedionas/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Pioglitazona , Ratos
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