Purpose

Isoniazid (INH) is prescribed both for the prophylaxis as well as the treatment of tuberculosis. It is primarily metabolized through acetylation by a highly polymorphic enzyme, N-acetyl transferase 2 (NAT2), owing to which significant variable systemic drug levels have been reported among slow and rapid acetylators. Furthermore, many drugs, like phenytoin, diazepam, triazolam, etc., are known to show toxic manifestation when co-administered with INH and it happens prominently among slow acetylators. Additionally, it is revealed in in vitro inhibition studies that INH carries noteworthy potential to inhibit CYP2C19 and CYP3A4 enzymes. However, CYP inhibitory effect of INH gets masked by opposite enzyme-inducing effect of rifampicin, when used in combination. Thus, distinct objective of this study was to fill the knowledge gaps related to gene-drug-drug interactions (DDI) potential of INH when given alone for prophylactic purpose.

Methods

Whole body-PBPK models of INH were developed and verified for both slow and fast acetylators. The same were then utilized to carry out prospective DDI studies with CYP2C19 and CYP3A4 substrates in both acetylator types.

Results

The results highlighted likelihood of significant higher blood levels of CYP2C19 and CYP3A4 substrate drugs in subjects receiving INH pre-treatment. It was also re-established that interaction was more likely in slow acetylators, as compared to rapid acetylators.

Conclusion

The novel outcome of the present study is the indication that prescribers should give careful consideration while advising CYP2C19 and CYP3A4 substrate drugs to subjects who are on prophylaxis INH therapy, and are slow to metabolic acetylation.

中文翻译：

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PBPK分析NAT2基因多态性对异烟肼药物相互作用潜力的影响

目的

异烟肼 (INH) 用于预防和治疗结核病。它主要通过高度多态性酶 N-乙酰转移酶 2 (NAT2) 的乙酰化代谢，因此在慢速和快速乙酰化剂中报告了显着可变的全身药物水平。此外，已知许多药物，如苯妥英、地西泮、三唑仑等，在与异烟肼共同给药时会表现出毒性表现，并且在慢乙酰化药物中表现突出。此外，它在体外被揭示抑制研究表明，INH 具有抑制 CYP2C19 和 CYP3A4 酶的显着潜力。然而，当联合使用时，INH的CYP抑制作用被利福平相反的酶诱导作用所掩盖。因此，本研究的不同目的是填补与单独用于预防目的的 INH 的基因-药物-药物相互作用 (DDI) 潜力相关的知识空白。

方法

开发并验证了 INH 的全身 PBPK 模型用于慢速和快速乙酰化剂。然后使用相同的方法对两种乙酰化剂类型中的 CYP2C19 和 CYP3A4 底物进行前瞻性 DDI 研究。

结果

结果强调了接受 INH 预处理的受试者血液中 CYP2C19 和 CYP3A4 底物药物水平显着升高的可能性。与快速乙酰化剂相比，慢速乙酰化剂更可能发生相互作用。

结论

本研究的新结果表明，处方者在向正在接受 INH 预防治疗且代谢乙酰化缓慢的受试者建议 CYP2C19 和 CYP3A4 底物药物时应仔细考虑。