Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug

Abstract

SQ109 is a novel [1,2]-diamine-based ethambutol (EMB) analog developed from high-throughput combinatorial screening. The present study aimed at characterizing its pharmacodynamics and pharmacokinetics. The antimicrobial activity of SQ109 was confirmed in vitro (Mycobacterium tuberculosis-infected murine macrophages) and in vivo (M. tuberculosis-infected C57BL/6 mice) and compared to isoniazid (INH) and EMB. SQ109 showed potency and efficacy in inhibiting intracellular M. tuberculosis that was similar to INH, but superior to EMB. In vivo oral administration of SQ109 (0.1-25 mg kg(-1) day(-1)) to the mice for 28 days resulted in dose-dependent reductions of mycobacterial load in both spleen and lung comparable to that of EMB administered at 100 mg kg(-1) day(-1), but was less potent than INH at 25 mg kg(-1) day(-1). Monitoring of SQ109 levels in mouse tissues on days 1, 14 and 28 following 28-day oral administration (10 mg kg(-1) day(-1)) revealed that lungs and spleen contained the highest concentration of SQ109, at least 10 times above its MIC. Pharmacokinetic profiles of SQ109 in mice following a single administration showed its C(max) as 1038 (intravenous (i.v.)) and 135 ng ml(-1) (p.o.), with an oral T(max) of 0.31 h. The elimination t(1/2) of SQ109 was 3.5 (i.v.) and 5.2 h (p.o.). The oral bioavailability was 4%. However, SQ109 displayed a large volume of distribution into various tissues. The highest concentration of SQ109 was present in lung (>MIC), which was at least 120-fold (p.o.) and 180-fold (i.v.) higher than that in plasma. The next ranked tissues were spleen and kidney. SQ109 levels in most tissues after a single administration were significantly higher than that in blood. High tissue concentrations of SQ109 persisted for the observation period (10 h). This study demonstrated that SQ109 displays promising in vitro and in vivo antitubercular activity with favorable targeted tissue distribution properties.

Figure 1

Chemical structures of EMB and SQ109.

Figure 2

Effects of tuberculosis drugs and SQ109 on RAW 264.7 cells infected with M. tuberculosis luciferase reporter strain H37Rv/pSMT1. Cells were treated with drugs for 7 days at various folds of their corresponding MICs: INH (1 MIC=0.73 μM), EMB (1 MIC=24 μM), SQ109 (1 MIC=1.56 μM). Results (mean±s.d., n=3) are expressed as RLU reading on day 7 relative to day 0 for the untreated control.

Figure 3

SQ109 concentrations (mean±s.d.) in the lung, spleen, kidney, liver, heart and plasma at 1 h after oral administration of the compound to mice (10 mg kg⁻¹ day⁻¹). Groups of 4–5 mice were killed on days 1, 14 and 28 during the 28-day dosing period. SQ109 concentrations in the lung, spleen and kidney were significantly higher than those in liver, heart and plasma (P<0.001). Statistically significant SQ109 accumulation in lungs and spleen was found on days 14 and 28 versus day 1: ^*P<0.05; ^**P<0.01.

Figure 4

Plasma concentration–time courses of SQ109 after i.v. (•, 3 mg kg⁻¹) and oral (○, 25 mg kg⁻¹) administration to mice. Each point represents the mean±s.d. of 4–5 mice.

Figure 5

Tissue levels of SQ109 after i.v. (3 mg kg⁻¹, upper panel) and p.o. administration (25 mg kg⁻¹, lower panel) to mice (mean±s.d., n=4–5). For clarity and comparison, the i.v. and p.o. scales were kept the same, resulting in the bars for stomach concentrations in the oral study being off scale. The actual stomach concentrations of SQ109 at 1 and 4 h were 934±300 and 376±183 μg g⁻¹, respectively.