Mechanism-based inhibition of CYP3A subfamilies by macrolide antibiotics and piperine.

Drug metabolism and bioanalysis letters Pub Date : 2022-08-04 DOI:10.2174/2949681015666220804103005

Toshiro Niwa, Risa Ishii

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Abstract

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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大环内酯类抗生素和胡椒碱对 CYP3A 亚家族的抑制机制。

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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Drug metabolism and bioanalysis letters

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1.60

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