Interspecies pharmacokinetics and in vitro metabolism of SQ109.
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 (t1/2) of SQ109 in dogs was longer than that in rodents, reflected by a larger volume of distribution (Vss) 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 [14C]SQ109 to rats, the highest level of radioactivity was in the liver, followed by the lung, spleen and kidney. Tissue-to-blood ratios of [14C]SQ109 were greater than 1. Fecal elimination of [14C]SQ109 accounted for 22.2% of the total dose of [14C]SQ109, while urinary excretion accounted for only 5.6%. The binding of [14C]SQ109 (0.1-2.5 microg 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 degrees C. The predominant metabolites in the human liver microsomes gave intense ion signals at 195, 347 and 363m/z, suggesting the oxidation, epoxidation and N-dealkylation of SQ109. P450 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.
Jia
Lee
L
Developmental Therapeutics Program, National Cancer Institute, NIH, 6130 Executive Blvd., Rm 8042, Rockville, MD 20852, USA. jiale@mail.nih.gov
Noker
Patricia E
PE
Coward
Lori
L
Gorman
Gregory S
GS
Protopopova
Marina
M
Tomaszewski
Joseph E
JE
D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology; D001798:Blood Proteins / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005029:Ethylenediamines / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D006899:Mixed Function Oxygenases / Q000502:physiology; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D014018:Tissue Distribution
D000995:Antitubercular Agents; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; C506841:N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D000218:Adamantane