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Table 2. Calculated pharmacokinetic parameters in male rats receiving a single dose of
r adiolabelled pyrimethanil
Radioactivity
Parameter
C max
(mg/kg)
T max
(h)
Half-life
(t1/2 h)
AUC
(mg/kg per h)
Clearance
(kg/h)
Lower dose (9.99 mg/kg bw) a
Total radioactivity 4.62 0.735 4.80 11.3 0.881
Pyrimethanil 0.625 0.607 1.24 8.08
SN 614 276 2.39 0.957 5.67 1.76
Higher dose (748 mg/kg bw) a
Total radioactivity 56.5 3.94 11.8 1080 0.707
Pyrimethanil 19.0 1.33 76.6 9.95
SN 614 276 15.3 1.29 71.5 10.7
From Challis (1995) and Jardinet (2006)
a
An average of three rats were used for each time-point.
AUC, area under the plasma concentration–time curve extrapolated to infinity; C max
, calculated maximum plasma
c oncentration; T max
, calculated time of maximum plasma concentration.
three females per cage). For the group at the lower dose, treated rats were killed (three males and three
females per group) at 1, 2, 4, 8, 12 and 24 h after dosing, while for the group at the higher dose, rats
were killed (three males and three females per group) at 2, 6, 10, 18, 24 and 48 h after dosing. Various
organs and tissues were removed and analysed for radioactivity. Blood was analysed for radioactivity.
Tissues were either combusted or solubilized. All samples were analysed for radioactivity by LSC.
Radiochemical purity was verified by thin-layer chromatography (TLC) and HPLC. The absorption
of pyrimethanil was rapid after the administration of a single low dose at 10 mg/kg bw by gavage
and pyrimethanil was widely distributed into the tissues. At the lower dose, peak concentrations of
radioactive residues were achieved by 1 h after dosing. With the exception of the gastrointestinal tract,
the highest concentrations were associated with the renal fat, thyroid, adrenals, liver, kidney and ovaries,
which also had tissue : plasma ratios of > 1 throughout the study. With the exception of the gonads, there
were no consistent significant differences in tissue concentrations of pyrimethanil between male and female
rats. At the higher dose (800 mg/kg bw), the peak concentrations of radioactivity were achieved in
tissues between 2 and 10 h after dosing and then declined slowly thereafter. With the exception of the 2-h
time-point, there were no consistent significant differences between the concentration of pyrimethanil
residues in the tissues of male and female rats at this dose. The highest concentrations of residues were
found in the renal fat, thyroid, adrenals, liver, kidney and ovaries. These tissues had tissue : plasma ratios
of > 1. The concentration of radioactive residues was one to three orders of magnitude greater than those
found in the rats at the lower dose, although the tissue distribution ratios were 1.5–8 times lower.
The half-lives of radiolabelled pyrimethanil and its metabolites in selected tissues (Table 3)
were independent of sex but were greater at the higher dose. The elimination half-lives in the plasma
were 5.41 and 5.23 and 8.22 and 11.69 in males and females at the lower and higher dose, respectively
(Whitby, 1995a, 1995b).
In a study of whole-body radioautography, groups of male and female Crl:CD(SD)BR rats
were given a single oral dose of [U-phenyl ring 14 C]pyrimethanil (purity, 98.8%) at 10 or 800 mg/kg
bw by gavage in an aqueous solution of 1% (w/v) gum tragacanth. One male and one female from
each group was killed at 45 min, 90 min, 3 h, 6 h, 12 h, 24 h or 48 h after dosing. The rats were frozen
and prepared for whole-body radioautography. Sagittal sections (about 25 µm thickness) were
then taken at six levels in order to visualize the major tissues and organs of the rat. After 21 or 42
PYRIMETHANIL 445–486 JMPR 2007