چکیده (انگلیسی):

Phenytoin (5,5-diphenylhydantoin; DPH) induces expression of cytochromes P450 (CYPs). Interactions
between DPH and tacrolimus suggested that the persistence of CYP induction
after discontinuation of DPH is dependent on the history of administration and dosing period
of DPH. However, the relationship between the duration of DPH administration and expression
of CYPs in the liver and small intestine of rats is not known. Alterations in levels of
P-glycoprotein (P-gp; MDR1; ABCB1) as well as CYPs cause drug interactions in the small
intestine.We examined the effects of the duration of DPH administration on expression of
CYPs and P-gp in the liver and small intestine of rats. Rats were treated with DPH (100 mg/kg,
peroral (p.o.) twice a day (b.d.)) for 2, 4, 8, and 16 d. mRNA levels of CYPs and P-gp were examined
using the total RNA extracted from the liver and duodenum 2 h and 24 h after the
final administration of DPH. CYP3A activities were determined using microsomes. DPH administration
for 2 d and 4 d markedly increased mRNA levels of CYPs such as CYP3A1, CYP3A2,
CYP2B1, and CYP2B2 in the liver. A relatively long duration of DPH administration (8 d and
16 d) resulted in abolition of the induction of hepatic CYP but increased CYP3A activities
were maintained. These results suggest that the duration of DPH administration could be
an important determinant of hepatic CYP induction.