title: Absorption, distribution and excretion of the anti-tuberculosis drug delamanid in rats: Extensive tissue distribution suggests potential therapeutic value for extrapulmonary tuberculosis.
abstract: Delamanid (OPC-67683, Deltyba™, nitro-dihydro-imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug-resistant tuberculosis. The absorption, distribution and excretion of delamanid-derived radioactivity were investigated after a single oral administration of14C-delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 h post-dose, and thereafter decreased slowly. Radioactivity levels were 3- to 5-fold higher in lung tissue at time to maximum concentration compared with plasma. In addition, radioactivity was broadly distributed in various tissues, including the central nervous system, eyeball, placenta and fetus, indicating that14C-delamanid permeated the brain, retinal and placental blood barriers. By 168 h post-dose, radioactivity in almost all the tissues was higher than that in the plasma. Radioactivity was also transferred into the milk of lactating rats. Approximately 6% and 92% of radioactivity was excreted in the urine and feces, respectively, indicating that the absorbed radioactivity was primarily excreted via the biliary route. No significant differences in the absorption, distribution and excretion of14C-delamanid were observed between male and female rats. The pharmacokinetic results suggested that delamanid was broadly distributed to the lungs and various tissues for a prolonged duration of time at concentrations expected to effectively target tuberculosis bacteria. These data indicate that delamanid, in addition to its previously demonstrated efficacy in pulmonary tuberculosis, might be an effective therapeutic approach to treating extrapulmonary tuberculosis. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shibata
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Shimokawa
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan.
authors.forename: Katsunori
authors.identifier: http://orcid.org/0000-0001-5618-4847
authors.initials: K
authors.lastname: Sasahara
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Yoda
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasabe
authors.affiliation: ADME & Tox. Research Institute, Sekisui Medical Co. Ltd, 2117 Muramatsu, Tokai-mura, Naka-gun, Ibaraki, 319-1182, Japan.
authors.forename: Mitsunari
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Umehara
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000652:urine; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005260:Female; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange; D008892:Milk / Q000737:chemistry; D009593:Nitroimidazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000652:urine; D010080:Oxazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000652:urine; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles
keywords: absorption; delamanid; distribution and excretion; extrapulmonary tuberculosis; rat