Metabolites in Photosafety Testing
Acknowledgments
1821
agreement with the phototoxic outcomes from in vitro/in vivo photo-
safety tests, suggesting the reliability of our photosafety prediction on
FF and FA. From these findings, phototoxic events related to FF would
be attributed to FA, which might be the reason for the discrepancy
between the observed phototoxicity after oral administration and the
negative results in the photopatch test of FF (Leenutaphong and
Manuskiatti, 1996).
The authors thank Philip Hawke (University of Shizuoka Scientific English
Program) for critical reading of and editorial assistance with this manuscript.
Authorship Contributions
Participated in research design: Kato, Suzuki, Ohtake, Onoue.
Conducted experiments: Kato, Suzuki, Ohtake.
Many drugs seemed to exhibit different PK behavior between
humans and nonhuman primates, which may partly be due to species
differences of metabolic enzymes such as cytochrome P450 enzymes,
esterases, and glucuronidases (Baillie and Rettie, 2011). FF is
metabolized into FA by carboxylesterase CES1A1 in the liver after
absorption, and a portion of it undergoes carbonyl reduction by
CYP3A4 to produce RFA, and these metabolites and their glucuronides
are then excreted (Weil et al., 1988, 1990; Cornu-Chagnon et al., 1995;
Miller and Spence, 1998; Fukami et al., 2010). Thus, outcomes from
PK assessment could not be completely extrapolated to humans as long
as interspecies differences existed in the enzymes related to FF
metabolism. According to a previous report, no significant differences
were reported between human and rat hepatic CES1A1 activity;
furthermore, plasma PK behavior of FA in humans was in agreement
with PK data in rats obtained in our study (Lovin et al., 2003; Taketani
et al., 2007). Thus, FA might also exhibit high dermal exposure in
humans as observed in rats. On the other hand, in humans, there
appeared to be interindividual variability in PK, efficacy, and safety
profiles of orally administered FF owing to the effect of food intake
(Davidson et al., 2005). Yun et al. (2006) demonstrated that the oral
administration of FF with a high-fat meal can cause significant
increases in Cmax and AUC0–‘ of FA compared with those under
fasted conditions in humans; hence, the effect of food intake, especially
high-fat meals, might have a major effect on the photosafety of oral FF
therapy since dermal exposure of FA might be increased when FF is
orally taken with high-fat meals.
Contributed new reagents or analytic tools: Kato, Seto, Onoue.
Performed data analysis: Kato, Onoue.
Wrote or contributed to the writing of the manuscript: Kato, Seto, Onoue.
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