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The results are summarized in Table 29. The metabolic profile in fetal-rat tissues is the same as
that in the plasma of non-pregnant and pregnant rats (Sugimoto, 2005e, 2005f). In rats, procymidone
was the major component in maternal plasma 6 h after the first dose, followed by PCM-NH-COOH
(and/or PCM-COOH) and PA-CH 2
OH but at all other sampling times, the main plasma metabolites
were PCM-NH-COOH (and/or PCM-COOH), PA-CH 2
OH and PA-COOH. Unchanged procymidone
was also the main component in the placenta and fetus 6 h after the first dose followed by PCM-
CH 2
OH. At other sampling times, however, PCM-CH 2
OH was the major component. PA-CH 2
OH
was also the main metabolite in amniotic fluid and its concentration increased with time. The transfer
ratios of metabolites showed that PCM-CH 2
OH accumulated more readily in the fetus than did
procymidone (Tomigahara, 2005d).
In rabbits, the main metabolites present in the fetus were procymidone and PCM-CH 2
OH. PCM-
COOH and PA-COOH, plus glucuronides of PCM-CH 2
OH and PA-CH 2
OH, were hardly transferred
to the fetus, although PA-COOH was the major component of maternal plasma (Sugimoto, 2005g).
In monkeys, procymidone was also the major component in the placenta and fetus, PCM-
CH 2
OH and/or PCM-COOH and PCM-NH-COOH were lesser metabolites. Other metabolites were
only detected at trace levels in fetuses (Mogi, 2005e).
These results show that the transfer of procymidone and metabolites to the fetus is significantly
greater (approximately 10-fold) in rats than in rabbits or monkeys. In rats, there was also a transfer of
PCM-CH 2
OH, the postulated developmental toxin, from the dam to the fetus.
Table 29. Pharmacokinetic parameters in plasma and tissues of pregnant rats, rabbits and
monkeys given oral doses of [phenyl- 14 C]procymidone at 125 mg/kg bw
Parameter Rats Rabbits Monkeys
Single dose Three doses Single dose Single dose
6 h 24 h 6 h 24 h 2 h 24 h 6 h 24 h
Dams
Concentration of 14 C (μg equivalent/g):
Plasma 18 28 35 30 40 2.3 5.5 3.7
Liver 53 56 — — 43 3.8 33 28
Kidney 32 59 — — 143 8.7 30 21
Whole fetus
Concentration of 14 C (μg equivalent/g):
Single dose 10 16 7.4 10 2.5 0.36 1.2 1.2
Three doses — — 21 15 — — — —
Ratio of concentrations of 14 C in whole
fetus and in maternal plasma
PCM 2.7 1.1 0.9 0.6 NM NM 0.5 0.8
PCM-CH 2
OH 16 10 48 22 2.1 NM 0.2 0.2
PCM-NH-COOH < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 0.4 0.2 0.2
PA-CH 2
OH 0.8 0.8 0.2 0.5 < 0.1 NF < 0.1