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qualitative autoradiography of TLC plates run with two solvent systems. The polar components were
reported to be glucuronides of hydroxyprocymidone (PCM-CH 2
OH) and hydroxyprocymidone acid
(PA-CH 2
OH). No radioactive compounds other than procymidone were detected in samples from the
controls. The hepatocytes came from four different donors and some variations were evident in the
autoradiograph patterns from different preparations (Tarui, 2005b).
Groups of four male, chimeric mice with humanized livers (i.e. liver repopulated with human
hepatocytes) (from PhoenixBio, Hiroshima, Japan) and four male mice (uPA -/- SCID) serving as controls
were given a single oral dose of [phenyl- 14 C]procymidone (purity, > 95%; specific activity,
15.8 MBq/mg) at 37.5 mg/kg bw in corn oil. Urine and faeces were collected at 24-h intervals for
72 h after dosing and analysed for radioactivity and for metabolites using high-performance liquid
chromatography (HPLC)/LSC and TLC/autoradiography. A glucuronidase/sulfatase preparation
(± glucuronidase inhibitor) was used to release conjugates, but only qualitative data were presented.
Radioactivity was excreted at similar rates in the urine and faeces of control and chimeric mice
(Table 5). The main difference in metabolism was the higher concentration of glucuronides (of PCM-
CH 2
OH and PA-CH 2
OH) and lower concentration of acid metabolites excreted in the chimeric mice
(Table 5) (Ohzone, 2005a).
Comparison of metabolism between species
Procymidone [phenyl- 14 C]procymidone (specific activity, 15.8 MBq/mg) and PCM-CH 2
OH
(specific activity, 3.3 MBq/mg) were incubated for 60 min at 37 0 C with S9 fractions prepared from
pooled livers of women (two Caucasians and one African-American), rats (Sprague-Dawley), rabbits
(New Zealand White) and monkeys (cynomolgus). A single concentration of 50μmol/l was used.
Metabolites were identified by co-chromatography with reference standards. Only limited information
was given in the study report. The rates of hydroxylation of procymidone (to alcohol or acid
derivatives) or oxidation of PCM-CH 2
OH (to acid derivatives) were relatively constant over the assay
period. S9 from rabbit liver had the highest activity for hydroxylation of procymidone, with activity
in rat liver being lower than that in other species (Table 6). S9 from monkey liver had the highest
activity for the oxidation of PCM-CH 2
OH, with the activity of S9 from rats being much lower than
that from other species tested (Table 6) (Matsui, 2005b).
Table 5. Metabolite excretion profiles in chimeric (humanized) mice (n = 4) and control mice (n = 4)
given [phenyl- 14 C]procymidone as a single dose at 37.5 mg/kg bw
Metabolite
Recovery (% of administered dose)
Chimeric mice a Control mice
Urine Faeces Urine Faeces
Excretion in 24 h 59 22 65 17
Excretion in 72 h 73 24 76 20
PCM (72 h) < 1 1.8 1.4 < 1
PCM-COOH (72 h) 21 4.6 34 6
PA-CH 2
OH (72 h) 2 < 1 2.5 1
PA-COOH (72 h) 12 2.6 26 3
Glucuronides (72 h) 35 7.5 7 2
Others/unextracted (72 h) 3 7 5 6
From Ohzone (2005a)
a
Chimeric mice possessed humanized livers (i.e. liver repopulated with human hepatocytes).
PA-CH 2
OH, hydroxyprocymidone acid; PA-COOH, carboxyprocymidone acid; PCM, procymidone; PCM-CH 2
OH,
hydroxyprocymidone; PCM-NH-COOH, carboxyprocymidone.
PROCYMIDONE 349–401 JMPR 2007