RESUMO
The preparative separation of dimetindene (CAS 5636-83-9) enantiomers was achieved by fractionated crystallization of the diastereomeric tartrate salts. HPLC on alpha-AGP (alpha 1-acid glycoprotein) was used for confirmation of the enantiomeric purity. After administration of the enantiomers to rats the AUC and Cmax of S(+) dimetindene and (-)N-demethyldimetindene were slightly increased. In agreement with the serum concentration data significantly more (-)N-demethyldimethindene was excreted into urine after administration of the individual enantiomers. S(+) dimetindene was metabolised to a lesser extent in vivo (see above) as well as in vitro in rat liver homogenate. After prior enzyme induction conversion of the enantioselectivity with respect to unmetabolised dimetindene occurred. 6-Methoxydimetindene, 6-hydroxydimetindene and 6-hydroxy-N-demethyldimetindene were synthesized. 6-Methoxydimetindene is likely to be a metabolite since the retention times of synthetic compound and the substance extracted from serum and urine are identical. The formation of 6-hydroxy-N-demethyldimetindene was proved for the first time by comparison of the mass spectra of metabolite isolated from in vitro incubations and synthetic compound after derivatisation with acetic anhydride.
Assuntos
Dimetideno/metabolismo , Antagonistas dos Receptores Histamínicos H1/metabolismo , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Dimetideno/farmacocinética , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Técnicas In Vitro , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Ratos , Ratos Endogâmicos , Ratos Sprague-Dawley , EstereoisomerismoRESUMO
Dimethindene and its metabolite N-demethyldimethindene were determined in human urine after dermal administration of dimethindene. The HPLC-method used was previously described. Data of 8 volunteers are presented. After 32 h an average of 0.023% of the administered dose of dimethindene and 0.022% of N-demethyldimethindene were excreted into urine. Since also after oral administration of dimethindene only about 1% of unmetabolised dimethindene is found in urine it can be concluded that a certain amount of dimethindene is absorbed through the skin after dermal administration.
Assuntos
Dimetideno/farmacocinética , Administração Cutânea , Dimetideno/administração & dosagem , Dimetideno/urina , Humanos , Absorção CutâneaRESUMO
The cytostatic drug ifosfamide (IFF) and its main metabolites 2-dechloroethyl ifosfamide (2-D-IFF) and 3-dechloroethyl ifosfamide (3-D-IFF) were isolated from the plasma matrix with high recovery by solid phase extraction using Bakerbond C18-cartridges. A further cleaning of the extracts is not necessary. An effective separation of IFF and metabolites from interfering compounds present in urine samples prior gc was performed with Extrelut-1 and dichloromethane/isopropanol (95:5, v/v). The described assays may be used for pharmacokinetic studies as well as drug monitoring in the clinical laboratory.
Assuntos
Ifosfamida/análogos & derivados , Ifosfamida/sangue , Ifosfamida/urina , HumanosRESUMO
A sensitive high-performance liquid chromatographic determination of dimethindene and its metabolite N-demethyldimethindene in urine has been developed. The quantitative analysis was followed by determination of the enantiomeric ratio of dimethindene on an alpha 1-AGP column (EnantioPac). The urinary data for nine volunteers after oral administration of racemic dimethindene are presented. The isolation, identification and synthesis of the metabolite N-demethyldimethindene are reported.