title: 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.
authors.affiliation: Developmental Therapeutics Program, National Cancer Institute/NIH, 6130 Executive Boulevard, Rockville, MD 20852, U.S.A. jiale@mail.nih.gov
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Tomaszewski
authors.forename: Colleen
authors.initials: C
authors.lastname: Hanrahan
authors.forename: Lori
authors.initials: L
authors.lastname: Coward
authors.forename: Patricia
authors.initials: P
authors.lastname: Noker
authors.forename: Gregory
authors.initials: G
authors.lastname: Gorman
authors.forename: Boris
authors.initials: B
authors.lastname: Nikonenko
authors.forename: Marina
authors.initials: M
authors.lastname: Protopopova
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002460:Cell Line; D003959:Diamines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004977:Ethambutol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D007275:Injections, Intravenous; D007538:Isoniazid / Q000008:administration & dosage / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D014018:Tissue Distribution; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D003959:Diamines; D004977:Ethambutol; D007538:Isoniazid