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首页> 外文期刊>Life sciences >EFFECTS OF CYTOCHROME P450 2E1 MODULATORS ON THE PHARMACOKINETICS OF CHLORZOXAZONE AND 6-HYDROXYCHLORZOXAZONE IN RATS
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EFFECTS OF CYTOCHROME P450 2E1 MODULATORS ON THE PHARMACOKINETICS OF CHLORZOXAZONE AND 6-HYDROXYCHLORZOXAZONE IN RATS

机译：细胞色素P450 2E1调节剂对大鼠体内氯唑啉酮和6-羟基氯唑啉酮药代动力学的影响

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摘要

A previously observed correlation between the rate of 6-hydroxylation of chlorzoxazone (CZX), a potent skeletal muscle relaxant, and cytochrome P450 2E1 activity in vitro led to the postulation that this drug may be used as a noninvasive probe for P450 2E1 activity in vivo. In this study, comparative pharmacokinetics of CZX and 6-hydroxychlorzoxazone (OH-CZX) were conducted in rats pretreated with an inhibitor or inducer of P450 2E1. After administration of CZX (150 mu mol/kg, i.v.) to rats, blood samples were taken at different time points and the plasma concentrations of CZX and OH-CZX were determined by HPLC. The concentrations for CZX and OH-CZX over time were simultaneously fitted to a model of first-order elimination of CZX and first-order formation and elimination of OH-CZX using the computer program PCNONLIN to give pharmacokinetic parameters. Diallyl sulfide, a P450 2E1 inhibitor, at an oral dose of 50 or 200 mg/kg 12 hr prior to the CZX dose markedly inhibited the hydroxylation of CZX. Pretreatment with ethanol (15% in the drinking water for six days), a condition known to induce P450 2E1, slightly enhanced the formation of OH-CZX. To observe possible involvement of enzymes other than P450 2E1 in CZX metabolism, dexamethasone and phenobarbital were also used. Pretreatment with dexamethasone (50 mg/kg, i.p. daily for four days) did not cause changes in CZX and OH-CZX pharmacokinetics. Pretreatment with phenobarbital (75 mg/kg, i.p. daily for three days) enhanced CZX metabolism slightly. Our results suggest that P450 2E1 plays a major role in CZX hydroxylation in rats, but other factors may also be involved in the metabolism in vivo. [References: 34]
机译：先前观察到的氯唑沙宗（CZX），强效骨骼肌松弛剂的6-羟基化速率与体外细胞色素P450 2E1活性之间的相关性导致推测该药物可以用作体内P450 2E1活性的非侵入性探针。在这项研究中，在用P450 2E1抑制剂或诱导剂预处理的大鼠中进行了CZX和6-羟基氯唑沙宗（OH-CZX）的比较药代动力学。将CZX（150μmol / kg，静脉内）给药于大鼠后，在不同的时间点采集血样，并通过HPLC测定CZX和OH-CZX的血浆浓度。使用计算机程序PCNONLIN将CZX和OH-CZX的浓度随时间的变化同时拟合到CZX的一级消除，OH-CZX的一级形成和消除的模型，以给出药代动力学参数。在CZX剂量之前的12小时，口服剂量为50或200 mg / kg的二烯丙基硫醚（一种P450 2E1抑制剂）显着抑制CZX的羟基化。用乙醇（在饮用水中占15％的六天时间）进行预处理（已知会诱导P450 2E1的条件）会略微提高OH-CZX的形成。为了观察除P450 2E1以外的酶可能参与CZX代谢，还使用了地塞米松和苯巴比妥。地塞米松（50 mg / kg，每天腹腔内连续四天）的预处理不会引起CZX和OH-CZX药代动力学的变化。苯巴比妥（75 mg / kg，每天腹腔内连续三天）预处理可略微增强CZX代谢。我们的结果表明，P450 2E1在大鼠CZX羟基化中起主要作用，但其他因素也可能参与体内代谢。 [参考：34]

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