Interspecies differences in
phenytoin (PHT) metabolism to
5-(4-hydroxyphenyl)-5-phenylhydantoin (
HPPH) were examined in human, cat and rat hepatic microsomes in vitro. Rat liver microsomes were 25 and 650 times more efficient at the conversion of PHT to
HPPH than human and cat liver microsomes, respectively.
Sulphaphenazole (83%) and
tolbutamide (TOL) (64%) were the most potent inhibitors of
HPPH formation in human liver microsomes, while
ciprofloxacin (27%),
enoxacin (27%) and TOL (26%) produced the greatest inhibition in cat liver microsomes. TOL was tested for its effect on
HPPH formation and
gingival overgrowth in cats in vivo. Eight cats received PHT
sodium (4 mg/kg/d) and another 8 cats received PHT
sodium together with TOL (20 mg/kg/d) for 10 wk. Six cats (75%) in the PHT group and 4 cats (50%) in the PHT & TOL group developed significant
gingival overgrowth by the end of the study. However, the extent and incidence of the overgrowth were similar in the 2 groups. There were no significant differences in mean AUC 0-10 weeks for plasma PHT (552.90 +/- 29.6 micrograms.d/mL [PHT alone] vs. 582.41 +/- 24.49 micrograms.d/mL [PHT & TOL]) and unconjugated
HPPH (1016.4 +/- 295.5 ng.d/mL [PHT alone] vs. 1174.5 +/- 397.2 ng.d/mL [PHT & TOL]) concentrations between the 2 groups of cats. Neither PHT nor
HPPH were detectable in the plasma of 8 rats which received PHT (4 mg/kg/d) over a 10-wk period. The rats showed no sign of gingival
inflammation (mean gingival index = 0) or
gingival overgrowth (mean
gingival overgrowth index = 0). Thirty-six adult epileptic patients on chronic PHT
therapy were examined; 17 (47%) of the patients demonstrated clinically significant overgrowth. The mean steady-state plasma PHT concentration was comparable to, and the mean plasma unconjugated
HPPH concentration 5-fold greater than, that observed in the cats. The results suggest that the rapid metabolism and elimination of PHT and
HPPH in the rat may enable it to become more resistant towards developing
gingival overgrowth, compared to the cat and man.