Inhibitory Potential of Twenty Five Anti-tuberculosis Drugs on CYP Activities in Human Liver Microsomes

Abstract

The direct inhibitory potential of twenty five anti-tuberculosis drugs on eight CYP-specific reactions in human liver microsomes was investigated to predict in vivo drug-drug interactions (DDIs) from in vitro data. Key words anti-tuberculosis drug; human liver microsome; CYP inhibition; drug-drug interaction Tuberculosis (TB) is a global health problem. In 2013, an estimated 9.0 million people developed TB and 1.5 million died from the disease, 360000 of whom were human immunodeficiency virus (HIV)-positive.1) Multidrug-resistant TB (MDR-TB) is defined as TB with resistance to at least isoniazid and rifampicin, the two most powerful first-line anti-TB drugs. 2)Current treatment regimens for MDR-TB are more toxic, last longer, and are less effective than treatment regimens for drugsensitive TB.3) In the development of combination regimens for TB and co-infection with TB and HIV, the prediction of drugdrug interactions (DDIs) helps to avoid the risk of adverse reactions caused by DDIs related to CYP enzymes.It is estimated that CYP enzymes are responsible for the metabolism of approximately three-quarters of the most prescribed drugs that are cleared by metabolism, including the anti-retroviral agents used to treat HIV. 4,5)

Pharmacokinetic interaction between bedaquiline and clofazimine in patients with drug-resistant tuberculosis

“…There are several possible explanations for the failure of the in vitro studies to predict a clinical drug-drug interaction between BDQ and CFZ. First, the in vitro studies used liver microsomes 4 or a liver cell line, 5 which are not as good as recombinant P450 enzymes in predicting clinical drug-drug interactions. 13 Second, in vitro studies are known to poorly predict clinical drug-drug interactions for drugs that are highly protein-bound, such as CFZ.…”

“…3 It is also widely used in other types of DR-TB. CFZ inhibits CYP3A4 in vitro, 4,5 but also weakly induces CYP3A4. 5 There are no published clinical data on pharmacokinetic (PK) drug-drug interactions between CFZ and substrates of CYP3A4 such as BDQ.…”

Traditional Preparations and Methanol Extracts of Medicinal Plants from Papua New Guinea Exhibit Similar Cytochrome P450 Inhibition

“…PIs inhibit CYP metabolism, a phenomenon which is often utilized to enhance pharmacokinetic profiles of other PIs taken concomitantly [22–24]. Common anti-TB drugs, such as isoniazid and rifapentine, have also been shown to cause CYP inhibition in vitro [25]. Excessive CYP inhibition can have negative consequences due to elevated concentrations of ARV or anti-TB drugs in the body [26, 27].…”

Potential drug–drug interactions between antiretroviral therapy and treatment regimens for multi-drug resistant tuberculosis: Implications for HIV care of MDR-TB co-infected individuals

“…Notably, isoniazid exhibits pronounced and dose-dependent inhibition of CYP3A4 and CYP2C19 at its therapeutic level (Desta et al, 2001). Additionally, isoniazid coadministration produced a 1.5 fold increase in AUC of triazolam (a substrate of CYP3A4) following a single oral dose ((26.5-38.6 ng h/ mL) (Shimokawa et al, 2015;Ochs et al, 1983).…”

“…The [I]max/Ki values of ethionamide on CYP1A2, CYP2B6, CYP2C19, CYP3A4 (M), and CYP3A4 (T) were 0.77, and those of prothionamide on CYP1A2, CYP2C9, CYP3A4 (M), and CYP3A4 (T) were 0.52. The highest [I]max/Ki value for ethionamide was 1.4 on CYP2C8, and the highest [I]max/ Ki values for prothionamide were 2.2, 1.8, and 1.3 on CYP2B6, CYP2C19, and CYP2C8, respectively, while thioacetazone exhibited mild CYP3A4 enzyme inhibition with a [I]max/K i value of only 0.14 (Shimokawa et al, 2015). CYP2B6 (the major metabolic pathway for efavirenz) is also induced by ethionamide.…”