Aqueous solubility and dissolution rate does not adequately predict in vivo performance: A probe utilizing some N-acyloxymethyl phenytoin prodrugs

Some physicochemical properties of N-acyloxyalkyl prodrugs of phenytoin wer e reported previously.(1,2) It was shown that despite their lower aqueous s olubilities relative to phenytoin, these lower-melting prodrugs with appare ntly disrupted crystalline structures gave either comparable or enhanced in vitro solubility and dissolution rate in simulated intestinal media made u p of bile salts and lecithin (SIBLM).(2) The current objective was to compa re the in vivo behavior of two of these prodrugs to phenytoin in dogs and a ttempt to correlate the in vitro behavior to their in vivo behavior. The or al bioavailability of phenytoin after administration of phenytoin (1) and t he selected prodrugs, 3-pentanoyloxymethyl 5,5-diphenylhydantoin (2) and 3- octanoyloxymethyl 5,5-diphenylhydantoin (3), in fed and fasted beagle dogs were compared to intravenously administered phenytoin. Phenytoin and its pr odrugs showed improvement in fed-state phenytoin bioavailability relative t o the fasted state indicating that food enhanced the delivery of phenytoin from phenytoin and its prodrugs. The increased bioavailability in the fed s tate may be due to stimulation of bile release by food and, for the prodrug s, possible catalysis of their dissolution by lipases.(3) In both, fasted a nd fed states, prodrugs 2 and 3 gave higher AUC values of phenytoin than th e parent compound. The enhanced bioavailability of phenytoin after oral adm inistration were more obvious in fed dogs. Although enhanced, AUC values of phenytoin from the prodrugs relative to phenytoin were not statistically d ifferent (at 95% confidence level) in fasted state, but were different in f ed state. Although the aqueous solubilities and dissolution of both prodrug s were lower than phenytoin, dissolution of 2 and 3 was equivalent and grea ter, respectively, relative to phenytoin in SIBLM. As expected, the in vivo behavior correlated better with the in vitro SIBLM dissolution behavior. T hese results indicate that aqueous solubility per se does not adequately pr edict in vivo behavior.