Biliary excretion of a glutathione conjugate of busulfan and 1,4-diiodobutane in the rat.
gamma-Glutamyl-beta-(S-tetrahydrothiophenium)alanyl-glycine, the glutathione-sulfonium conjugate of busulfan and 1,4-diiodobutane, was identified in the bile of rats following intravenous administration of equimolar doses of either compound. The glutathione-sulfonium conjugate was synthesized from 1-bromo-4-chlorobutane and characterized by 1H and 13C NMR and FAB/MS. An HPLC method was developed to identify the conjugate from rat bile by pre-column fluorescent derivatization with o-phthalaldehyde. The biliary excretion of cyclic sulfonium conjugates was quantitated indirectly by measuring the release of tetrahydrothiophene (THT) after treatment of the bile with base. THT release was quantitative and was measured by gas chromatography. With busulfan, peak biliary concentrations of THT-releasing metabolite(s) were reached after 90 min and 26% of the dose of busulfan was recovered in the bile after 8 hr. When diiodobutane was administered, 21% of the dose was recovered, and the peak concentration was reached in 30 min. The decline in THT releasing metabolite(s) was more rapid with 1,4-diiodobutane, and THT was no longer measurable after 3.5 hr compared to 7.5 hr after busulfan administration. These data confirm that busulfan and other 1,4-disubstituted butanes are conjugated with glutathione in vivo.
D000818:Animals; D001646:Bile / Q000378:metabolism*; D002066:Busulfan / Q000378:metabolism*; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005978:Glutathione / Q000378:metabolism*; D006847:Hydrocarbons, Iodinated / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013452:Sulfonium Compounds / Q000378:metabolism
D006847:Hydrocarbons, Iodinated; D013452:Sulfonium Compounds; C039721:1,4-diiodobutane; D002066:Busulfan; D005978:Glutathione