Chlorzoxazone ; blood ; Chromatography, High Pressure Liquid ; methods ; Cytochrome P-450 CYP2E1 ; blood ; Humans

OBJECTIVETo investigate the effect of CYP450 enzyme inhibition of berberine in pooled human liver microsomes by cocktail probe drugs.

METHODCocktail probe drugs method has been established, an LC-MS/MS analytical method has been established to determine the five probes of midazolam, phenacetin, dextromethorphan, tolbutamide, chlorzoxazone and the internal standard was benzhydramine to evaluate the effect of CYP450 activity following administration of berberine in pooled human liver microsomes.

RESULTCompared with control group, the pharmacokinetics of midazolam, phenacetin and tolbutamide were no significant differences, but the pharmacokinetics of chlorzoxazone was significantly decreased. There were no significant differences for the pharmacokinetics of dextromethorphan when the concentration of berberine was 50 microg x L(-1). The pharmacokinetics of dextromethorphan was significantly decreased when the concentration of berberine was exceed 200 microg x L(-1).

CONCLUSIONBerberine has no influence on the activities of CYP3A4, CYP1A2 and CYP2C19 below 2 000 microg x L(-1), but can inhibit the activity of CYP2E1 and CYP2D6 in concentration-dependent.

Berberine ; pharmacology ; Chlorzoxazone ; pharmacokinetics ; Cytochrome P-450 Enzyme Inhibitors ; Dextromethorphan ; pharmacokinetics ; Dose-Response Relationship, Drug ; Humans ; Microsomes, Liver ; enzymology ; Midazolam ; pharmacokinetics ; Phenacetin ; pharmacokinetics ; Tolbutamide ; pharmacokinetics

Cytochrome P450 2E1 (CYP2E1) is involved in the toxicity and carcinogenicity of a number of solvents and xenobiotics. Like the various types of oxidation pharmacogenetics, the activity of the enzyme shows a discernible interindividual and interethnic variation. However, no pharmacogenetic information on CYP2E1 polymorphism has been available from a Korean population. The aim of this study was to explore the pharmacogenetics of CYP2E1 polymorphism in a native Koreans after an oral 400 mg dose of chlorzoxazone administered to 128 subjects. Urine samples were collected during the subsequent 8-hour period and urinary concentrations of chlorzoxazone and 6-hydroxychlorzoxazone were determined by a high performance liquid chromatography with an ultraviolet detector. The limit of detection in the samples was found to be 0.5 mug/ml. The mean value of the 6-hydroxychlorzoxazone excreted in 8 hr urine expressed as the percentage was 48.2 13.8%. The frequency distribution of percentage of the administered dose excreted as the 6-hydroxy metabolite was unimodally distributed in the subjects studied. However, the values showed wide (7-fold) interindividual difference, ranged from 11.6% to 79.8% of the dose of chlorzoxazone. Thus, it was considered that the pharmacogenetic characteristics of CYP2E1 in a Korean population did not-represent multimodal distribution in the 6-hydroxychlorzoxazone excreted in 8-hr urine expressed as the percentage. And the activity of the CYP2E1 in a Korean population seemed to be less compared with that of the Caucasian subjects.
Asian Continental Ancestry Group ; Chlorzoxazone ; Chromatography, Liquid ; Cytochrome P-450 CYP2E1* ; Cytochrome P-450 Enzyme System* ; Cytochromes* ; Humans ; Limit of Detection ; Pharmacogenetics ; Solvents ; Xenobiotics

This study aimed to explore the impact of depression caused by chronic unpredictable mild stress (CUMS) on in vivo activity of six kinds of CYP450 isoforms in rats. According to 'Katz' method, the model of CUMS was established. Tolbutamide, chlorzoxazone, theophylline, midazolam, omeprazole and dextromethorphan were chosen as probe substrates of CYP2C6, CYP2E1, CYP1A2, CYP3A2, CYP2D1 and CYP2D2 of rats. Plasma concentration of six kinds of CYP450 in control group and model group were determined by LC-MS/MS and computed pharmacokinetic parameters. Consequently, metabolism of theophylline and chlorzoxazone accelerated significantly (P < 0.01), but tolbutamide, dextromethorphan, omeprazole and midazolam had no significant difference. The present study proved that depression caused by CUMS had strong induction to CYP1A2 and medium induction to CYP2E1.
Animals ; Chlorzoxazone ; metabolism ; Chromatography, Liquid ; Cytochrome P-450 Enzyme System ; metabolism ; Depression ; Dextromethorphan ; metabolism ; Liver ; enzymology ; Midazolam ; metabolism ; Omeprazole ; metabolism ; Rats ; Stress, Physiological ; Tandem Mass Spectrometry ; Theophylline ; metabolism ; Tolbutamide ; metabolism

OBJECTIVETo study the effect of ferment powder caterpillar fungus on cytochrome P450 isozymes CYP1A2, CYP3A4 and CYP2E1.

METHODThe methods of Cocktail probe drugs were used. The rats were randomly divided into two groups. One group were given ferment powder caterpillar fungus once daily orally for ten days. Another group received orally normal saline one daily as the blank control. After ten days of treatment, the rats were given probe drugs of coffine, dapsone and chlorzoxazone and the blood was taken out by femoral catheterization. The plasma concentration of probe drugs were determined by HPLC. Data of plasma drug level-time were disposed with DAS Ver 2.0.

RESULTThe metabolism of caffeine and dapsone speeded up after receiving ferment powder caterpillar fungus, but the metabolism of chlorzoxazone was hardly changed.

CONCLUSIONIt suggested that ferment powder caterpillar fungus tended to be the inducer of CYP1A2 and CYP3A4. But the CYP2E1 was hardly affected.

Animals ; Caffeine ; metabolism ; Chlorzoxazone ; metabolism ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System ; metabolism ; Dapsone ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; Fermentation ; Male ; Random Allocation ; Rats ; Rats, Wistar