Investigation of (Oxodioxolenyl)methyl carbamates as nonchiral bioreversible prodrug moieties for chiral amines.

The preparation of (oxodioxolenyl)methyl carbamates and their evaluation as novel nonchiral prodrug moieties for chiral primary and secondary amino functional drugs are described. 4-(Carbamoylmethyl)-2-oxo-1,3-dioxolene derivatives of 3,4-dimethoxyphenethylamine with 5-methyl, 5-phenyl, and 5-anisyl substitution (5a, 5b, and 5c) on the dioxolenone ring were prepared as model amine prodrugs by a one step process involving displacement of p-nitrophenol from appropriately substituted ring opening of these carbamates led to a cascade reaction resulting in the rapid and quantitative regeneration of the parent amine drug. Aryl substitution did not significantly alter the hydrolysis rates of these dioxolenone carbamates in buffers at pH 1 and 7.4 or in rat plasma, although the hydrolysis rates of 5-phenyl- (1b) and 5-anisyl- 4-methyl-1,3-dioxol-4-en-2-one (1c) in pH 7.4 phosphate buffer were 2-3 fold faster than that of the 5-methyl-substituted analog (1a). Application of this prodrug strategy to the chiral fibrinogen receptor antagonist L-734,217 resulted in a prodrug that gave quantitative reconversion in rat and dog plasma in vitro and oral bioavailability of 23 +/- 6% in dogs for the parent drug.

Investigation of N-[(acyloxy) alkyl] ester as a prodrug model for drugs containing the phenyltetrazole moiety.

N-Acyloxyalkylation using 5-phenyltetrazole as a model compound was investigated as a general means of prodrug modification of the tetrazole ring with a view to change the physicochemical properties for improving biomembrane transport. Pivaloxymethylation gave a mixture of 1- and 2- [(pivaloxy)methyl] -5-phenyltetrazole isomers in 1:4 ratio. The structures of the compounds were established by NMR spectroscopy using nuclear Overhauser effect (NOE) difference and heteronuclear multiple bond correlation (HMBC) techniques. The second-order rate constants for hydroxide ion catalyzed hydrolysis of the ester functions of both the isomers were nearly the same, though the two isomers differ in the degree of conjugation between the tetrazole and the aromatic rings as a result of the differences in the extent to which the two rings can assume coplanarity. The values of the second-order rate constants were comparable to those reported for other N-[(pivaloxy)methyl]-substituted compounds, such as derivatives of 5-fluorouracil, indicating that the unique electronic properties of the tetrazole ring do not have a significant effect on the rate of base-catalyzed hydrolytic regeneration of 5-phenyltetrazole, or the potential stability of such prodrugs. However, the hydrolysis of the more sterically hindered 1-[(pivaloxy)methyl] ester in rat plasma was slower than that of the 2-substituted isomer.

Application site dependent ocular absorption of timolol.

Ocular absorption of timolol in rabbits was studied after topical ocular administration of 3H-timolol in an eyedrop or in silicone cylindrical devices that released timolol at 7.2 micrograms/h. The devices were applied in either the inferior or superior conjunctival sac. Timolol concentrations were nearly equal in the inferior and superior portions of ocular tissues when the drug was administered in an eyedrop. Administration in the devices resulted in unequal timolol distribution in the cornea, conjunctiva, sclera, and iris-ciliary body. Timolol concentrations were higher in the part of each tissue that was closer to the site of the device application. Unequal concentrations of timolol in the superior and inferior part of the eye and very low timolol concentrations in the aqueous humor indicated that timolol was absorbed mainly via a noncorneal route from the device placed in the inferior conjunctival sac. Induced blinking at one minute intervals did not change ocular absorption of timolol. Compared with inferior conjunctival sac applications, placement of the devices in the superior conjunctival sac resulted in increased corneal and total ocular absorption of timolol as indicated by higher timolol concentrations in the aqueous humor and by a smaller difference between concentrations in the superior and inferior portions of the examined tissues. The application site dependent ocular absorption indicated that controlled release of timolol in the tear fluid did not result in a uniform timolol distribution in the preocular tear fluid of rabbit eyes.

Systemic delivery of timolol after dermal application: Transdermal flux and skin irritation potential in the rat and dog.

Timolol, a beta-adrenergic antagonist, was evaluated for transdermal flux with rat skin in vitro and with the dog in vivo. Skin irritation after dermal application of timolol was assessed in the rat in vivo. Drug flux across rat skin in vitro ranged between 2 and 110 µg cm(-2) hr(-1), dependent on the formulation. The transdermal flux of timolol in the dog was greater than 10 µg cm(-2) hr(-1). This estimate was based on the degree of antagonism of isoproterenol challenge following transdermal administration of timolol relative to that obtained following intravenous administration of timolol. Irritation was observed in the rat after occluded dermal application of timolol free base but was not observed when the concentration of the drug in the formulation was decreased.

Bisulfite-ion-catalyzed degradation of fluorouracil.

5-Fluorouracil (I) reversibly adds bisulfite ion across its greater than C5 equals C6 smaller than bond to form 5-fluoro-5,6-dihydrouracil-6-sulfonate (II). The pH-independent equilibrium constant for this reaction was calculated to be 560 M-1 at ionic strength 1.00 M at 25 degrees. Compound II was observed to be unstable in alkaline solution and reacted to yield uracil-6-sulfonic acid, fluoride ion, and alpha-fluoro-beta-ureidopropionic acid-beta-sulfonate (III), along with I (via a loss of HSO3 minus). In strongly alkaline conditions, i.e., 1 M NaOH, III was observed to undergo a subsequent reaction to produce a compound believed to be alpha-fluoro-beta-ureidoacrylic acid (V) or fluoromalonaldehydic acid (VII). These irreversible degradation reactions of II lead to a complete degradation of I in sodium bisulfite solutions. The similarity of this bisulfite-ion-catalyzed degradation of I to its hydrolytic degradation is discussed.