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EC number: 220-778-7
CAS number: 2896-70-0
4-Oxo tempo is assimilated rapidly via the oral gavage route but no accumulation occurs. Indications are that the substance is rapidly metabolism in the liver and other tissues by a reductive mechanism.
rapid oral assimilation of Oxo Tempo is demonstrated by the acute oral
toxicity study in the rat where the acute toxicity of 1464 mg/kg
indicated a relatively low acute toxicity. Oxo tempo is readily soluble
in water and was administered in aqueous solution. Signs of toxicity
were seen within 30 minutes of administration at doses of 1414 and 2000
mg/kg and deaths occurred between 1 and 4 hours of administration in
these groups. Clinical signs were minimal at 1000 mg/kg and no deaths
occurred at this dose.
subsequent 28 day repeat dose study demonstrated little indication of
toxicity at the maximum dose of 1000 mg/kg/day. Increased absolute and
relative liver weight indicated a possible work hypertrophy response. In
a recovery group, the increased liver weight was shown to resolve within
acute oral LD50 test indicates a steep dose response curve. The
lethal body burden seen in the acute study is not reached by repeat
dosages in the 28 day study and tends to indicate that there is rapid
assimilation and excretion, with no accumulation.
metabolism of Oxo Tempo has been investigated in several in-vivo and
et al (1994) used EPR spectroscopy to track the disappearance of the
electron spin signature of Oxo Tempo following intravenous
administration of 0.13 – 0.22 mmol/kg to mice in vivo. Oxo
Tempo was postulated to be metabolised to a hydroxylamine metabolite
which does not possess an EPR spin signature. The disappearance of the
EPR spin signal was monitored in vivo in the tail of the mouse using a
non invasive technique. The
T1/2for this process was determined to be 3 minutes
indicating a very rapid in-vivo metabolism, however no identification of
the metabolites was determined in this study.
and Borchart (1999) used an isolated perfused rat liver system to
investigate actual metabolites of oxo tempo. In their experimental
system they saw rapid disappearance of the parent oxo tempo with
approximately 30% only remaining after 3 hours. They identified 5
metabolites. The primary metabolite being tempol (the reduced OH
derivative), plus the 1-hyrdoxyl forms of both oxo tempo and tempol and
their sterically hindered secondary amines. Whilst
the rate of metabolism of the parent is not as rapid as that seen by
Komerov et al., it is still rapid. The difference might indicate that
whilst the liver is one site of metabolism it may not be the only site
and thus the whole body metabolism seen in the in-vivo mouse may be a
more accurate reflection of the half life.
using P450inhibitors, Kroll and Borchart also determined the
metabolism was independent of cytochrome P450.
and Langer et al (1998) investigated the metabolism of oxo tempo by
isolated human kerationcytes (cell line HaCaT). The
metabolism of oxo tempo in this system confirms that the liver is not
the only metabolic site and so strengthens the kinetic data taken from
the intact in-vivo mouse. They determined that the metabolism was
inhibited by a thiol blocking agent and postulated a mechanism dependent
on the flavoenzyme thioredoxin reductase.
acute and sub acute, in vivo rodent studies indicate that oxo tempo is
assimilated rapidly via the oral gavage route but that no accumulation
occurs. In-vivo and in-vitro studies indicate a rapid metabolism in the
liver and other tissues by a reductive mechanism. Actual
excretion of parent or metabolites has not been demonstrated, however
the 28 day repeat dosing study, with a 14 day recovery phase would
indicate that oxo tempo is quantitatively excreted within a 24 hour
period, or that the metabolites have negligible toxicity.
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