CYP3A4型
CYP2C19型
异烟肼
药理学
药品
药物遗传学
CYP2D6型
药物相互作用
药代动力学
利福平
医学
药物代谢
化学
酶
细胞色素P450
肺结核
基因型
生物化学
基因
病理
作者
Ankit Balhara,Saranjit Singh
标识
DOI:10.1007/s11095-021-03095-9
摘要
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.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.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.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.
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