{"title":"大环内酯类抗生素和胡椒碱对 CYP3A 亚家族的抑制机制。","authors":"Toshiro Niwa, Risa Ishii","doi":"10.2174/2949681015666220804103005","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>The mechanism-based inhibition of macrolide antibiotics, such as erythromycin and clarithromycin, and piperine on testosterone 6β-hydroxylation activities by cytochrome P450 (CYP) 3A4, polymorphically expressed CYP3A5, and fetal CYP3A7 were compared.</p><p><strong>Methods: </strong>6β-Hydroxy testosterone was determined by high-performance liquid chromatography.</p><p><strong>Results: </strong>Although preincubation with erythromycin and clarithromycin decreased CYP3A4-meditaed testosterone 6β- hydroxylation in a time-dependent manner, and the estimated maximum inactivation rate constant (k inact ) and the inactivation rate constant reaching half of k inact (K i ) for erythromycin were approximately 1/2 and 1/5, respectively, of those for clarithromycin. Obvious preincubation time-dependent inhibition of erythromycin against CYP3A5 and CYP3A7 was not observed. Piperine exhibited preincubation time- dependent inhibition, and the calculated K i and k inact values for CYP3A4 were approximately 1/7 and 1/2, respectively, of those for CYP3A5.</p><p><strong>Conclusion: </strong>It is speculated that the preincubation-dependent inhibition by piperine would be more potent in CYP3A5 non-expressors than CYP3A5-expressors.</p>","PeriodicalId":72844,"journal":{"name":"Drug metabolism and bioanalysis letters","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2022-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mechanism-based inhibition of CYP3A subfamilies by macrolide antibiotics and piperine.\",\"authors\":\"Toshiro Niwa, Risa Ishii\",\"doi\":\"10.2174/2949681015666220804103005\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>The mechanism-based inhibition of macrolide antibiotics, such as erythromycin and clarithromycin, and piperine on testosterone 6β-hydroxylation activities by cytochrome P450 (CYP) 3A4, polymorphically expressed CYP3A5, and fetal CYP3A7 were compared.</p><p><strong>Methods: </strong>6β-Hydroxy testosterone was determined by high-performance liquid chromatography.</p><p><strong>Results: </strong>Although preincubation with erythromycin and clarithromycin decreased CYP3A4-meditaed testosterone 6β- hydroxylation in a time-dependent manner, and the estimated maximum inactivation rate constant (k inact ) and the inactivation rate constant reaching half of k inact (K i ) for erythromycin were approximately 1/2 and 1/5, respectively, of those for clarithromycin. Obvious preincubation time-dependent inhibition of erythromycin against CYP3A5 and CYP3A7 was not observed. Piperine exhibited preincubation time- dependent inhibition, and the calculated K i and k inact values for CYP3A4 were approximately 1/7 and 1/2, respectively, of those for CYP3A5.</p><p><strong>Conclusion: </strong>It is speculated that the preincubation-dependent inhibition by piperine would be more potent in CYP3A5 non-expressors than CYP3A5-expressors.</p>\",\"PeriodicalId\":72844,\"journal\":{\"name\":\"Drug metabolism and bioanalysis letters\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-08-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug metabolism and bioanalysis letters\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2174/2949681015666220804103005\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug metabolism and bioanalysis letters","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/2949681015666220804103005","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
目的比较红霉素、克拉霉素等大环内酯类抗生素和胡椒碱对细胞色素 P450（CYP）3A4、多态表达的 CYP3A5 和胎儿 CYP3A7 的睾酮 6β 羟基化活性的抑制机制：结果：虽然红霉素和克拉霉素预孵育会以时间依赖的方式降低 CYP3A4 介导的睾酮 6β- 羟基化，但红霉素的最大灭活速率常数（k inact）和达到 k inact一半的灭活速率常数（K i）分别约为克拉霉素的 1/2 和 1/5。没有观察到红霉素对 CYP3A5 和 CYP3A7 有明显的抑制作用。胡椒碱表现出抑制作用的预孵育时间依赖性，计算得出的 CYP3A4 K i 和 k inact 值分别约为 CYP3A5 的 1/7 和 1/2：结论：推测胡椒碱对 CYP3A5 非表达者的预孵育依赖性抑制作用比对 CYP3A5 表达者的抑制作用更强。
Mechanism-based inhibition of CYP3A subfamilies by macrolide antibiotics and piperine.
Objective: The mechanism-based inhibition of macrolide antibiotics, such as erythromycin and clarithromycin, and piperine on testosterone 6β-hydroxylation activities by cytochrome P450 (CYP) 3A4, polymorphically expressed CYP3A5, and fetal CYP3A7 were compared.
Methods: 6β-Hydroxy testosterone was determined by high-performance liquid chromatography.
Results: Although preincubation with erythromycin and clarithromycin decreased CYP3A4-meditaed testosterone 6β- hydroxylation in a time-dependent manner, and the estimated maximum inactivation rate constant (k inact ) and the inactivation rate constant reaching half of k inact (K i ) for erythromycin were approximately 1/2 and 1/5, respectively, of those for clarithromycin. Obvious preincubation time-dependent inhibition of erythromycin against CYP3A5 and CYP3A7 was not observed. Piperine exhibited preincubation time- dependent inhibition, and the calculated K i and k inact values for CYP3A4 were approximately 1/7 and 1/2, respectively, of those for CYP3A5.
Conclusion: It is speculated that the preincubation-dependent inhibition by piperine would be more potent in CYP3A5 non-expressors than CYP3A5-expressors.
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