Population pharmacokinetics of ethionamide in patients with tuberculosis

Pharmacokinetics and tissue distribution studies of orally administered nanoparticles encapsulated ethionamide used as potential drug delivery system in management of multi-drug resistant tuberculosis

“…Drug-loaded nanoparticles (equivalent to 130 mg/kg and 260 mg/kg of ethionamide) illustrated a prolonged drug release profile for up to 6 days in comparison to only 6 h for free ethionamide (Figure 2). The drug levels were also maintained above the MIC (0.6 µg/ ml; Zhu et al, 2002) for 5 days in the case of encapsulated ethionamide at both doses as compared to 2 h for free ethionamide. The pharmacokinetic parameters derived from plasma concentration-time profiles are summarized in Table 5.…”

“…It is available only as conventional release tablets given daily at doses of 0.5-1 g (Zhu et al, 2002). Daily dosing of anti-tubercular drug for prolonged periods is known to cause non-compliance and treatment failure which in turn leads to MDR TB and XDR TB (extensively drug resistant tuberculosis).…”

Metabolism of the Antituberculosis Drug Ethionamide

“…ETH PK parameters were independent of age, weight, height, gender, and creatinine clearance [31]. Tuberculosis patients appeared to have lower volumes of distribution (3.22 L/Kg) and clearance values (1.88 L/h/Kg) compared to healthy volunteers ( Table 1).…”

“…The PK parameters of ETH are given in Table 1. PK parameters differed between healthy subjects and tuberculosis patients, resulting in a lower AUC for tuberculosis patients, possibly due to a decrease in bioavailability [13,31]. …”

A synthetic mammalian gene circuit reveals antituberculosis compounds

“…EthR-mediated repression of ethA transcription requires rather high clinical doses of ethionamide [up to 1g/day (6, 18)], which is associated with severe side effects including neurotoxicity (19) and fatal hepatotoxicity (6), yet is often still insufficient to reach minimum inhibitory levels in the bloodstream (20). Therefore, 2-phenylethyl-butyrate-triggered dissociation of EthR from the ethA promoter resulting in derepression of ethA, which was confirmed by quantitative RT-PCR of ethA transcripts (2.93 Ϯ 0.04-and 9.7 Ϯ 1.7-fold increase in the presence of 0.5 and 2 mM 2-phenylethyl-butyrate, respectively), may increase the sensitivity of Mycobacterium to ethionamide-based therapy.…”