RT Journal Article
SR Electronic
T1 Metabolites of Hexamethyldisiloxane and Decamethylcyclopentasiloxane in Fischer 344 Rat Urine—A Comparison of a Linear and a Cyclic Siloxane
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 206
OP 214
DO 10.1124/dmd.31.2.206
VO 31
IS 2
A1 Sudarsanan Varaprath
A1 Joan M. McMahon
A1 Kathleen P. Plotzke
YR 2003
UL http://dmd.aspetjournals.org/content/31/2/206.abstract
AB Hexamethyldisiloxane (MM or HMDS) and decamethylcylclopentasiloxane (D5) are examples of a linear and a cyclic siloxane, respectively. These volatile low molecular weight siloxanes are of significant commercial importance. To aid in the pharmacokinetic investigations, major metabolites of MM and D5 were identified in urine collected from Fischer (F-344) rats administered [14C]MM and [14C]D5 orally and via intravenous injection. The metabolite profiles were obtained using a high-pressure liquid chromatography (HPLC) system equipped with a radioisotope detector. The metabolite elution was carried out on a C18 column using an acetonitrile/water mobile phase. The structural assignments were based on GC-MS analysis of the tetrahydrofuran extract of urine containing the metabolites. Some of the metabolites in the extracts were first protected with trimethylsilyl groups prior to GC-MS analysis using bis(trimethylsiloxy)trifluoroacetamide or highly purified hexamethyldisiloxane. The structures were also confirmed by comparisons with synthetic 14C-labeled metabolite standards. The following are among the major metabolites identified in the case of MM: Me2Si(OH)2, HOMe2SiCH2OH, HOCH2Me2SiOSiMe2CH2OH, HOMe2SiOSiMe2CH2-OH, HOCH2Me2SiOSiMe3, and Me3SiOH. The metabolites of D5 are as follows: Me2Si(OH)2, MeSi(OH)3, MeSi(OH)2OSi(OH)3, MeSi(OH)2OSi(OH)2Me, MeSi(OH)2OSi(OH)Me2, Me2Si(OH)OSi(OH)Me2, Me2Si(OH)OSiMe2OSi(OH)Me2, nonamethylcyclopentasiloxanol, and hydroxymethylnonamethylcyclopentasiloxane. No parent MM or D5 was present in urine The presence of certain metabolites such as HOMe2SiCH2OH and Me2Si(OH)2 in MM and D5, respectively, clearly established the occurrence of demethylation at the silicon-methyl bonds. Metabolites of the linear siloxane are structurally different from that obtained for cyclic siloxane except for the commonly present Me2Si(OH)2. Mechanistic pathways for the formation of the metabolites were proposed. The American Society for Pharmacology and Experimental Therapeutics