RESUMO
The Japanese Society for the Study of Xenobiotics has focused on drug development and clinical pharmacotherapy by applying cutting-edge technology and reviewing drugs. One specific area of focus has been the reverse-translational approach. This approach uses data from the investigation of clinical problems and from the detailed revisiting of preclinical studies to discover new pharmacotherapies and new methods to prevent drug-induced side effects. In 2017, the U.S. Food and Drug Administration restricted the use of prescription codeine cough-and-cold medicines in children. This decision was based on concerns about the effects of the extensive metabolite morphine in cytochrome P450 2D6 ultra-rapid metabolizers. However, there are few reports on the side effects of dihydrocodeine in Japanese children. Our laboratory measured serum concentrations of dihydrocodeine in a 1-month-old infant with respiratory depression who was given dihydrocodeine phosphate in a suspected case of overdosing. Levels of dihydrocodeine and its primary metabolite, dihydromorphine, were high in this infant. However, the molar ratios of glucuronide conjugates of dihydrocodeine and dihydromorphine were lower than those found in a 3-year-old and a 6-year-old child used as references. To support and facilitate reverse-translational research, the elimination of regional differences in the methodologies used for liquid chromatography to measure drug concentrations and for the genotyping of drug-metabolizing enzymes should become the focus in hospitals, laboratories, and doctoral programs.
Assuntos
Sociedades Científicas/organização & administração , Pesquisa Translacional Biomédica , Xenobióticos , Criança , Pré-Escolar , Codeína/administração & dosagem , Codeína/efeitos adversos , Codeína/análogos & derivados , Codeína/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Di-Hidromorfina/sangue , Descoberta de Drogas , Tratamento Farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Lactente , JapãoRESUMO
A sensitive and specific method was developed for the determination of dihydrocodeine and its metabolite dihydromorphine in human serum using codeine and morphine as internal standards. Measurement is performed with GC-tandem MS after one simple extraction step and derivatization to the pentafluoropropionic esters. Sensitivity of the method is excellent and allows for the reproducible quantification of dihydrocodeine and dihydromorphine with limits of quantification of 2 ng/ml and 40 pg/ml serum, respectively. The method is therefore well suited for investigation of the pharmacokinetics and the metabolism of dihydrocodeine.
Assuntos
Codeína/análogos & derivados , Di-Hidromorfina/sangue , Cromatografia Gasosa-Espectrometria de Massas/métodos , Codeína/sangue , Codeína/farmacocinética , Di-Hidromorfina/farmacocinética , Cromatografia Gasosa-Espectrometria de Massas/normas , Cromatografia Gasosa-Espectrometria de Massas/estatística & dados numéricos , Humanos , Morfina , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A quick, sensitive and accurate high-performance liquid chromatographic method for morphine measurement in plasma has been developed using an unmodified silica column with a non-aqueous ionic eluent. Small plasma samples (0.4 ml) were extracted with a liquid-liquid extraction column and dihydromorphine was used as internal standard. The limit of quantitation was 2 ng/ml. The electrochemical detector was capable of detecting 150 pg of morphine. A calibration line with a correlation of 0.9994 +/- 0.00026 was produced over the range 2-80 ng/ml.
