Bile Salt–Fatty Acid Mixed Micelles as Nasal Absorption Promoters. III. Effects on Nasal Transport and Enzymatic Degradation of Acyclovir Prodrugs

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The absorption enhancement and presystemic degradation kinetics of a homologous series of acyclovir 2′-ester prodrugs were investigated in rats using the in situ nasal perfusion technique in the presence of bile salt–fatty acid mixed micells. In vitro incubation studies indicated that nasal perfusate containing a mixed micellar solution generated higher ester-cleaving activity than isotonic phosphate buffer washings. Inhibitor screening and substrate specificity studies demonstrated the enzyme to be most likely carboxylesterase rather than true cholinesterase. The extent of prodrug cleavage by the carboxylesterase appears to correlate well with the substrate li-pophilicity for esters with linear acyl chains. On the other hand, branching of the acyl side chain significantly retards acyclovir pro-drug breakdown. To estimate the nasal epithelial membrane and cytoplasmic damaging effect caused by sodium glycocholate (NaGC)–linoleic acid (15 m M:5 m M) mixed micelles, the release profiles of 5′-nucleotidase (5′-ND), lactate dehydrogenase (LDH), and carboxylesterase in the nasal perfusate were measured as a function of time. The results indicated that the activities of all three enzymes resulting from the mixed micellar solution appeared to be significantly higher than those caused by 15 m M NaGC alone. The apparent nasal absorption rate constants of acyclovir and its butyrate, valerate, pivalate, and hexanoate ester prodrugs in mixed micellar solutions containing an esterase inhibitor (1 mM phenylmethylsulfonyl fluoride) were individually calculated. Without an inhibitor, lengthening of the linear acyl side chain of the prodrug resulted in greatly accelerated degradation coupled with moderate absorption improvement. The solubilities and micellar binding constants of acyclovir prodrugs were also determined. Mixed micelles composed of 15 m M NaGC and 5 m M linoleic acid are incapable of incorporating these esters into the micellar cavity, although NaGC micelle alone can actively solubilize them in a concentration-dependent manner.

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