TABLE 4

Metabolites of 14C-Ruboxistaurin in Human Plasma, Urine, and Feces after a Single Oral 64-mg (100 μCi) Dose of 14C-Ruboxistaurin Mesylate to Healthy Male Subjects (n = 6)

Matrixa
Peak No.
Metabolite I.D.b
M + H +
Product Ions (m/z)
P U F Ruboxistaurin Embedded Image 469 451, 424, 406, 398, 384, 289, 98, 84, 58
P U F 1 N-Desmethyl [LY338522] 455 424, 412, 406, 398, 384, 289, 84
P U F 2 N,N-Didesmethyl [326986] 441 424, 423, 406, 398, 384, 289, 70
F 29 Alcohol [326651] N-dealkylation 442 424, 399, 384, 371, 353, 339, 313
U F 10c 21-Hydroxy-N-desmethyl 471 453, 440, 428, 414, 197, 184, 156, 84
U F 17d A-ring hydroxy-N-desmethyl 471 454, 440, 428, 414, 289, 84
U 9e 2-Hydroxy-N-desmethyl 471 454, 428, 414, 271, 176, 169, 157, 145, 84
U F 5d,f 7-Hydroxy-N-desmethyl 471 453, 440, 428, 414, 396, 289, 84
U F 15d B-ring hydroxy-N-desmethyl 471 453, 440, 428, 414, 305, 84
U F 8e 2-Hydroxy-N-desmethyl 471 453, 440, 414, 271, 176, 169, 157, 145, 84, 70
U F 11c 21-Hydroxy-N-desmethyl 471 453, 440, 197, 184, 156, 84
U F 12 21-Hydroxy 485 440, 422, 412, 400, 324, 184, 156, 98, 84, 58
U F 28 g 2-Hydroxy [2053556] 485 440, 414, 396, 384 271, 176, 169, 145, 84, 58
P U F 3d,f 7-Hydroxy 485 467, 440, 422, 414, 289, 98, 84, 58
U F 14d B-ring hydroxy 485 440, 305, 98, 84
F 16d A-ring hydroxy 485 440, 422, 414, 289, 84, 58
P U 6 d , f N→O on dimethylamino 485 468, 467, 424, 289, 98, 84, 58
U 27 + O2 501 483, 456, 438, 84, 58
U
18
+ O + glucuronide
661
485, 440

  • h Metabolite 18 has been identified as the glucuronide of hydroxylated parent but the MS/MS data were not sufficient to determine the site of hydroxylation.

  • ↵ a P = plasma, U = urine, and F = feces.

  • ↵ b The underlined metabolites in the table have been confirmed with either NMR or comparison with standards.

  • ↵ c Metabolites 10 and 11 product ion spectra suggest hydroxylation of the 21-position of indole ring B.

  • ↵ d Metabolites that have the m/z 289 product ion have been hydroxylated on the indole ring A and, conversely, those with a m/z 305 ion have been hydroxylated on the indole ring B.

  • ↵ e The MS/MS product ion spectra for 8 and 9 are consistent with the two diastereomers of N-desmethyl 2053556. Metabolites 8 and 9 have the m/z 145, 169, 176, and 271 product ions consistent with hydroxylation of the 2-position of indole ring A in the keto form.

  • ↵ f Metabolite structures for 3, 5, and 6 have been determined with NMR (Barbuch et al., 2006).

  • ↵ g Metabolite 28 has been identified as LY2053556 based on its MS/MS product ion spectrum and its relative retention time compared with the standard. Metabolite 28 has m/z 145, 169, 176, and 271 ions, consistent with hydroxylation at the 2-position of indole ring A (Barbuch et al., 2006).