Metabolism studies of the antischistosomal drug praziquantel using tandem mass spectrometry: distribution of parent drug and ten metabolites obtained from control and schistosome-infected mouse urine.
The collisionally activated dissociation spectrum of the antischistosomal drug praziquantel (PZQ) has many structure-specific fragmentations which permit identification of PZQ and seventeen of its hydroxylated metabolites in mouse urine. These fragmentations may also be used to quantify the metabolic pattern of PZQ. In the present study, a triple-quadrupole mass spectrometer system has been used to generate [M + H]+ ions for PZQ and its monohydroxy, dihydroxy and trihydroxy metabolites which yield daughter ions capable of quantifying PZQ and ten of these metabolites. The goal of these experiments was to evaluate the effect of this hepatic infection on drug metabolism. This was accomplished in two steps. First, the amount of unmetabolized, mono- and dihydroxylated PZQ was established from the [M + H]+ ions. Then the specific metabolites at each level of hydroxylation were determined from daughter ion spectra. The product of these two values produces the metabolite pattern. The reproducibility of these assays ranged from good, with a coefficient of variation of 3% for the most abundant metabolite, to poor (43%) for PZQ, which is only 1% of the total elimination pattern. The excretion of unchanged PZQ and two dihydroxylated metabolites was enhanced in animals bearing schistosomiasis compared to control mice, while a third dihydroxylated metabolite was depressed.
Ali
M H
MH
Department of Pharmacology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037.
Abramson
F P
FP
Fetterolf
D D
DD
Cohn
V H
VH
D000818:Animals; D001711:Biotransformation; D005260:Female; D006900:Hydroxylation; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D011223:Praziquantel / Q000652:urine*; D012555:Schistosomiasis mansoni / Q000652:urine*
D011223:Praziquantel