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Interspecies pharmacokinetics and in vitro metabolism of SQ109
Author(s) -
Jia Lee,
Noker Patricia E,
Coward Lori,
Gorman Gregory S,
Protopopova Marina,
Tomaszewski Joseph E
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706650
Subject(s) - pharmacokinetics , bioavailability , volume of distribution , chemistry , pharmacology , oral administration , adme , microsome , metabolism , in vivo , urine , absorption (acoustics) , excretion , spleen , kidney , distribution (mathematics) , feces , endocrinology , medicine , in vitro , biology , biochemistry , mathematical analysis , physics , microbiology and biotechnology , mathematics , acoustics , paleontology
This study aimed at characterizing the interspecies absorption, distribution, metabolism and elimination (ADME) profile of N ‐geranyl‐ N ′‐(2‐adamantyl)ethane‐1,2‐diamine (SQ109), a new diamine‐based antitubercular drug. Single doses of SQ109 were administered (intravenously (i.v.) and per os (p.o.)) to rodents and dogs and blood samples were analyzed by liquid chromatography tandem mass spectrometry (LC/MS/MS). Based on i.v. equivalent body surface area dose, the terminal half‐life ( t 1/2 ) of SQ109 in dogs was longer than that in rodents, reflected by a larger volume of distribution ( V ss ) and a higher clearance rate of SQ109 in dogs, compared to that in rodents. The oral bioavailability of SQ109 in dogs, rats and mice were 2.4–5, 12 and 3.8%, respectively. After oral administration of [ 14 C]SQ109 to rats, the highest level of radioactivity was in the liver, followed by the lung, spleen and kidney. Tissue‐to‐blood ratios of [ 14 C]SQ109 were greater than 1. Fecal elimination of [ 14 C]SQ109 accounted for 22.2% of the total dose of [ 14 C]SQ109, while urinary excretion accounted for only 5.6%. The binding of [ 14 C]SQ109 (0.1–2.5 μ g ml −1 ) to plasma proteins varied from 6 to 23% depending on the species (human, mouse, rat and dog). SQ109 was metabolized by rat, mouse, dog and human liver microsomes, resulting in 22.8, 48.4, 50.8 or 58.3%, respectively, of SQ109 remaining after a 10‐min incubation at 37°C. The predominant metabolites in the human liver microsomes gave intense ion signals at 195, 347 and 363 m / z , suggesting the oxidation, epoxidation and N ‐dealkylation of SQ109. P 450 reaction phenotyping using recombinant cDNA‐expressed human CYPs in conjunction with specific CYP inhibitors indicated that CYP2D6 and CYP2C19 were the predominant CYPs involved in SQ109 metabolism.British Journal of Pharmacology (2006) 147 , 476–485. doi: 10.1038/sj.bjp.0706650