Influence of pregnancy and folic acid on phenytoin metabolism by rat liver microsomes.

Liver microsomal suspensions from pregnant and nonpregnant Sprague-Dawley rats were assayed for NADPH-dependent metabolism of phenytoin to the hydroxylated products, 5-(rho-hydroxyphenyl)-5-phenylhydantoin (rhoHPPH) and 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)5-phenylhydantoin (H2DIOL). UDP-glucuronic acid-dependent glucuronyltransferase activity for conjugating rhoHPPH was also measured. The specific activity for formation of rhoHPPH decreased by 35% in 21-day pregnant rats compared with nonpregnant rats, whereas specific activity for production of H2DIOL was increased approximately 2-fold on the 7th and 14th but not the 21st day of pregnancy. Because of a 25% increase in liver weight during pregnancy, the total hepatic phenytoin hydroxylase activity in pregnant rats (day 21) was not significantly different from that of nonpregnant controls. Folic acid treatment during pregnancy prevented the decrease in phenytoin hydroxylase specific activity. The KM for production of either rhoHPPH or H2DIOL was similar (90 micrometer) in pregnant (day 21) and nonpregnant animals. Thus, overall hepatic microsomal enzyme activity for metabolizing phenytoin was not significantly reduced during pregnancy in rats, although the ratio of H2DIOL to rhoHPPH was increased during the first two weeks. Folic acid may play a role in pregnancy-associated changes in phenytoin hydroxylase activity.