Biopharmaceutical studies on hydantoin derivatives. V. Pharmacokinetics and pharmacodynamics of 5,5-diphenylhydantoin and 1-benzenesulfonyl-5,5-diphenylhydantoin.
Disposition of 1-benzenesulfonyl-5,5-diphenylhydantoin (II) having a potent anti-inflammatory activity was compared with that of 5,5-diphenylhydantoin (I), an antiepileptic drug, in order to elucidate whether the pharmacodynamic difference between them can be explained by their physicochemical and pharmacokinetic properties. After oral administration of I-14C to rats, radioactivity was distributed in all tissues including the brain, whereas after II-14C administration, the concentrations of radioactivity in most tissues were lower than those in plasma. The results were consistent with the finding obtained by whole-body autoradiography which revealed that after oral administration of II-14C to rats, radioactivity was not transferred into brain but was significantly transferred into inflamed tissues. Brain/plasma concentration ratio of I was about 1.3, whereas that of II was about 0.05. Plasma protein binding of I having pKa value of 8.30 was about 88%, whereas that of II having pKa value of 4.89 was about 99%. The changes in physicochemical properties due to introduction of a benzenesulfonyl group into the hydantoin ring may be responsible for the difference in the disposition between I and II. When II was cerebroventricularly administered to mice, it showed a potent anti-convulsant activity against maximal electroshock seizure, the activity being comparable to that for I. This indicates that the earlier failure to demonstrate the activity of II in a routine screening test for antiepileptic drugs was due to the inability of II to penetrate the blood-brain barrier and to achieve effective concentration in the brain. II was found to inhibit the biosynthesis of prostaglandin. These findings along with the physicochemical properties suggest that although II does not fall structurally under any category of anti-inflammatory drugs the mechanism of action may be similar to that for non-steroidal acidic anti-inflammatory drugs.
Fujioka
H
H
Tan
T
T
Kishi
M
M
Miyazaki
H
H
Masuda
Y
Y
Yokoyama
Y
Y
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000008:administration & dosage / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D015232:Dinoprostone; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008099:Liver / Q000378:metabolism; D008297:Male; D008617:Mephenytoin / Q000031:analogs & derivatives / Q000378:metabolism; D051379:Mice; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D011458:Prostaglandins E / Q000096:biosynthesis; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D000927:Anticonvulsants; D011458:Prostaglandins E; C049546:1-benzenesulfonyl-5-ethyl-5-phenylhydantoin; C003109:PC-796; C014544:ethylphenylhydantoin; D010672:Phenytoin; D015232:Dinoprostone; D008617:Mephenytoin