Interspecies pharmacokinetics and in vitro metabolism of SQ109

1 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. 2 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 and3.8%, respectively. 3 After oral administration of [C-14] SQ109 to rats, the highest level of radioactivity was in the liver, followed by the lung, spleen and kidney. Tissue-to-blood ratios of [C-14] SQ109 were greater than 1. Fecal elimination of [C-14] SQ109 accounted for 22.2% of the total dose of [C-14] SQ109, while urinary excretion accounted for only 5.6%. The binding of [C-14] SQ109 (0.1 - 2.5 mu g ml(-1)) to plasma proteins varied from 6 to 23% depending on the species ( human, mouse, rat and dog). 4 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 degrees 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. P450 reaction phenotyping using recombinant cDNA-expressedhuman CYPs in conjunction with specific CYP inhibitors indicated that CYP2D6 and CYP2C19 were the predominant CYPs involved in SQ109 metabolism.