ABSTRACT
<p><b>OBJECTIVE</b>To study the changes of pharmacokinetics of 6,7-dimethoxycoumarin in a rat model of alpha-naphthylisothiocyanate (ANIT)-induced experimental hepatic injury after oral administration of Yinchenhao Decoction (, YCHD) using an ultra pressure liquid chromatography (UPLC) method.</p><p><b>METHODS</b>Rats were divided into a normal group and a model group, after modeled by 4% ANIT (75 mg/kg) for 48 h, they were orally administrated with YCHD extract at the dose of 0.324 g/kg, and then blood was collected from their orbital sinus after different intervals. Changes in liver function were monitored by the levels of liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST)] and bilirubins [total bilirubin (TBIL), direct bilirubin (DBIL)], the concentration of 6,7-dimethoxycoumarin in plasma were measured by UPLC, and the pharmaceutical parameters were calculated with DAS2.1.1 software.</p><p><b>RESULTS</b>The concentration-time curve of both normal and modeled rats after oral administration of YCHD was obtained. Their time to maximum plasma concentration (t(max)) were both 0.25 h, the maximum concentration (C(max)) were 4.533 μg/mL and 6.885 μg/mL, and their area under concentration-time curve (AUC)(0→24h) were 16.272 and 32.981, respectively. There was a 51.88% and 100.46% increase in C(max) and AUC(0-t) (P<0.05), but there showed a 45.52% and 92.93% reduction in clearance of drug and volum of distribution (P<0.05), respectively.</p><p><b>CONCLUSIONS</b>Hepatic injury could significantly influence the pharmacokinetics of 6,7-dimethoxycoumarin after oral administration of YCHD, the absorption and distribution process was accelerated in liver injured rats, but the metabolism and elimination process was slowed. And this may lead to a significant accumulation of 6,7-dimethoxycoumarin in the body.</p>
Subject(s)
Animals , Rats , 1-Naphthylisothiocyanate , Administration, Oral , Chemical and Drug Induced Liver Injury , Blood , Drug Therapy , Metabolism , Coumarins , Blood , Pharmacokinetics , Disease Models, Animal , Drug Evaluation, Preclinical , Drugs, Chinese Herbal , Pharmacokinetics , Therapeutic Uses , Liver , Models, Biological , Rats, Sprague-Dawley , Validation Studies as TopicABSTRACT
Objective To detect the mutation of ATP7A gene in 2 families with Menkes disease.Met-hods Genomic DNA of 6 members from 2 families were extracted with salt fractionation.The encoding exons and 2 sides flanking intron of ATP7A gene were amplified from genomic DNA of the probands and their parents by PCR and directly sequence.Light microscope was used to test the hair of probands and normal healthy children.Results Proband 1 had a deletion mutation of c.3 045del T in exon 14 of ATP7A gene and resulted in a stop codon just several nucleotides behind the deletion site.His mother was a heterozygote of the mutation and had normal phenotype.Proband 2 had a nonsense mutation of c.2 956 in exon 14 of ATP7A gene and resulted in a stop of amino acid synthesis.His mother was not a heterozygote of the mutation.Genetype and phenotype in fathers of the 2 probands were normal.Hair of the probands in light microscope were tenuity,midheaven,the color of hair also turned to light.Conclusions The c.3 045del T mutation of ATP7A gene cause the phenotype of Menkes disease in proband 1.His mother is a heterozygote of the disease without symptoms and he is of familial inheritance.The c.2 956 nonsense mutation of ATP7A gene cause the phenotype of Menkes disease in proband 2.His mother is not a heterozygote of the disease and he is not of familial inheritance.