Niwa Toshiro, Ishii Risa
School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan.
Drug Metab Bioanal Lett. 2022 Aug 4. doi: 10.2174/2949681015666220804103005.
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.
6β-Hydroxy testosterone was determined by high-performance liquid chromatography.
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.
It is speculated that the preincubation-dependent inhibition by piperine would be more potent in CYP3A5 non-expressors than CYP3A5-expressors.
比较基于机制的大环内酯类抗生素（如红霉素和克拉霉素）以及胡椒碱对细胞色素P450（CYP）3A4、多态性表达的CYP3A5和胎儿CYP3A7睾酮6β-羟化活性的抑制作用。
采用高效液相色谱法测定6β-羟基睾酮。
虽然红霉素和克拉霉素预孵育能以时间依赖性方式降低CYP3A4介导的睾酮6β-羟化作用，且红霉素的估计最大失活速率常数（kinact）和达到kinact一半的失活速率常数（Ki）分别约为克拉霉素的1/2和1/5。未观察到红霉素对CYP3A5和CYP3A7有明显的预孵育时间依赖性抑制作用。胡椒碱表现出预孵育时间依赖性抑制作用，CYP3A4的计算Ki值和kinact值分别约为CYP3A5的1/7和1/2。
推测胡椒碱的预孵育依赖性抑制作用在CYP3A5非表达者中比在CYP3A5表达者中更强。
