Stereoselective inhibition of diphenylhydantoin metabolism by p-hydroxyphenyl-phenylhydantoin enantiomers in rats.
Different doses of rac-p-HPPH (0.4 and 4 mg/h) were given repeatedly to rats infused with [14C]phenytoin. The serum levels of 14C-labeled and unlabeled p-HPPH, and [14C]phenytoin were measured by an HPLC method and radiometric analysis. The clearance of phenytoin and p-HPPH was determined by rate of dosing divided by the steady-state concentration. The phenytoin clearance was significantly lower in the high dose p-HPPH injection group than in the low dose group (87 versus 262 ml/h), whereas p-HPPH clearance showed no difference. The formation clearance of [14C]p-HPPH was also significantly lower in rats injected with high dose of p-HPPH (35 versus 169 ml/h). The clearance of other elimination pathways was also lower in rats with high dose of p-HPPH (53 versus 89 ml/h). The serum protein binding of phenytoin was lower in rats injected with high dose of p-HPPH. The result indicated that injections of rac-p-HPPH mainly inhibited on the formation of p-HPPH itself. The formation of (R)-p-HPPH and (S)-p-HPPH in microsomal preparation was measured by a ligand-exchange chromatographic method. The formation of (S)-p-HPPH or (R)-p-HPPH was not only inhibited by the enantiomer itself, but also cross-inhibited by the other enantiomer. To the formation of either (S)-p-HPPH or (R)-p-HPPH, (S)-p-HPPH showed a higher inhibitory activity. The use of rac-p-HPPH to inhibit phenytoin metabolism in vivo involved several mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Huang
J D
JD
Department of Pharmacology, National Cheng Kung University, Medical College, Taiwan, Republic of China.
Hsieh
C Y
CY
D000818:Animals; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
C001419:hydroxyphenytoin; D010672:Phenytoin