Premium
Quantitative Tissue Distribution and Pharmacokinetics of IW‐1973, a Novel Clinical‐Stage sGC Stimulator, After Oral Administration in Rats
Author(s) -
Banijamali Ali,
Wakefield James,
Barden Tim,
Carvalho Andrew,
Zimmer Daniel R,
Currie Mark,
Hall Katherine,
Solon Eric,
Masferrer Jaime,
Ribadeneira Maria
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.666.7
Subject(s) - pharmacokinetics , cyclic guanosine monophosphate , kidney , nitric oxide , guanosine , distribution (mathematics) , adipose tissue , pharmacology , medicine , lung , soluble guanylyl cyclase , oral administration , endocrinology , chemistry , cyclic gmp , biochemistry , mathematical analysis , mathematics
Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine‐5′‐triphosphate (GTP) to the secondary messenger cyclic guanosine‐3′,5′‐monophosphate (cGMP) upon binding of nitric oxide (NO). IW‐1973 is a sGC stimulator in clinical development that binds to sGC and enhances NO signaling resulting in an increase in cGMP production. Oral administration of IW‐1973 has been associated with elevations of cGMP‐sGC signaling in many different tissues including liver. Preclinical and clinical studies have shown that sGC stimulators relax smooth muscle, lower blood pressure, and have anti‐fibrotic effects. sGC stimulators with high distribution to tissues may have particular relevance for the treatment of vascular and fibrotic diseases of the lung, heart, liver, and kidney. The tissue distribution and pharmacokinetics (PK) of total radioactivity in male Long‐Evans rats was evaluated by quantitative whole‐body autoradiography (qWBA) following administration of a single oral (PO) dose of 3 mg/kg and 200 μCi/kg [ 14 C]IW‐1973. T max was 1 h post‐dose and the t 1/2 of total plasma radioactivity was 23.7 h. Analysis of tissues at various timepoints post‐dose revealed rapid and widespread distribution of [ 14 C]IW‐1973‐derived radioactivity. Tissue concentrations in 19 of 44 tissues were observed to be higher than in plasma at all timepoints. Of particular interest were the high tissue to plasma AUC all ratios observed for liver (172), white adipose (28), brown adipose (15), kidney (5–7), heart (5), and lung (3); and the distinctly lower ratios observed in the bone (0.4) and pigmented eye lens (0.1). The preferential tissue distribution of IW‐1973 to organs such as liver and kidney may be a favorable property to treat not only vascular diseases but also those associated with extensive tissue inflammation and fibrosis. Support or Funding Information Ironwood Pharmaceuticals