| The routes by which drugs may be metabolized or biotransformed are many and varied and include the chemical reactions of oxidation, reduction, hydrolysis, hydration, conjugation and condensation. It is important that these pathways are studied as the route of metabolism of a drug can determine whether it shows any pharmacological or toxicological activity. Drug metabolism is normally divided into two phases, phase I (or functionalisation reactions) and phase II (or conjugative reactions). The reactions of phase I are thought to act as a preparation of the drug for the phase II reactions, i.e. phase I "functionalises" the drug by producing or uncovering a chemically reactive group on which the phase II reactions can occur. Thus, the phase II reactions are usually the true "detoxification" pathways and give products that account for the bulk of the inactive, excreted products of a drug.Cytochrome P450 (CYP) is one of the most important representatives of drug metabolism enzymes, and plays a key role in the metabolic inactivation/activation of numerous exogenous and endogenous. CYP exists mainly in liver microsomes. CYP superfamily shows wide range, poor selectivity, large structure difference, inter-individual variation, overlapping substrate specificities in exogenous metabolism and can be easily induced and inhibited by a number of chemical compounds. There is, therefore, a great probability of competition between drugs and endogenous compounds for the same enzyme, between different enzymes for the same substrate and between two drugs for the same enzyme. Meanwhile, many drugs are not only the substrate of the enzyme, but also the inducer or inhibitor of the enzyme or others. Thismay change the pharmacological and toxicological effects of drug itself or other drugs, which is one of the reasons resulting in drug interaction in pharmacokinetics. Testing for drug-drug interactions has been the subject of a FDA guidance document in 1997. At present, in order to decrease the risk in the development of new drugs, the international pharmaceutical factories have enhanced the research of absorption, distribution, metabolism, excretion and toxicology.Diphenytriazol is a new non-hormonal and non-prostaglandin candidate agent, can terminate pregnancy in all species so far investigated and can inhibit the ovariocarcinoma cell. It has potent pharmacological activity, low toxicity and wide security range, may have good clinical prospect. In this paper, the interaction of diphenytriazol and CYP is studied using the in vitro metabolism tests. This research can provide some scientific evidences, which can instruct clinical secure and efficient medication. The text was divided into four parts to evaluate the in vitro metabolism of diphenytriazol, the inductive effect and inhibitive effect of diphenytriazol on rat liver cytochrome P450, and the metabolism interaction of diphenytriazol with other drugs. 1. In vitro metabolism of diphenytriazol in rat liver microsomesAIM: To obtain the information about metabolic mechanism of diphenytriazol by liver enzymes, the metabolism of diphenytriazol in rat liver microsomes in vitro was investigated. METHODS: To establish a reversed-phase high-performance liquid chromatography (RP-HPLC) method for determination of diphenytriazol in rat liver microsomes. The metabolism of diphenytriazol was investigated in five kinds of rat liver microsomal incubate pretreated with phenobarbital (PB), dexamethasone (Dex), p-naphthoflavone (BNF), diphenytriazol and control. Diphenytriazol was incubated in different rat liver microsomes, extracted by chloroform, and diazepam was used as internal standard. The concentration of remaining substrate in microsomal incubates was determined by reversed-phase high-performance liquid chromatography (RP-HPLC). RESULTS: The assay was linear from 3.62 to 362.0umol-L~l for diphenytriazol in rat liver microsomal incubates. The average exaction recovery and method recovery was (91.7 5.0)% and (100.7 1.9)% (n=6), intra-day and inter-dayvariation coefficients were less tha... |
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