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Purpose: The objective of this study was to synthesize anhydride prodrugs for prolong action to shield the carboxylic acid group from irritative effects and to temporary hydrophobize the drug so that it becomes accessible to aqueous media when the anhydride residue is hydrolyzed., Methods: Ibuprofen, a nonsteroidal anti-inflammatory agent, was used as a representative drug for anhydride derivatization. Mixed anhydrides of ibuprofen with fatty acids of different chain length were prepared by reacting acid chloride derivatives with the corresponding acid in the presence of acid acceptor and two-phase reaction. Mixed anhydrides were also prepared by dehydration reaction using acetic anhydride and anhydride interchange of symmetric anhydrides. The analgesic effects of mixed anhydride prodrugs were tested using nonsteroidal anti-inflammatory drug rat paw edema model. In vitro degradation of mixed anhydrides and drug release were monitored by high-performance liquid chromatography., Results: Ibuprofen was bound to aliphatic and aromatic acids via an anhydride bond in high reaction yields (>85%) with high mixed anhydride content (>80%). The mix anhydride was purified by chromatography and stored at 4 degrees C to minimize conversion into the symmetric anhydride. These anhydride derivatives hydrolyzed at different time intervals depending on the hydrophobicity of conjugated acid. In vivo testing of the ibuprofen anhydride derivatives for analgesic effect indicated an extended action of the drug for over 24 h as a function of the fatty acid chain length., Conclusion: This study demonstrates the promise of anhydride prodrugs for extending drug action and shielding the carboxylic acid group.

Purpose: In order to evaluate the in vivo penetration of prodrugs which undergo metabolism in skin, we analyzed the in vivo penetration profiles of acyclovir prodrugs based on a two-layer skin diffusion model in consideration of metabolic process., Methods: Acyclovir prodrugs (e.g., valerate, isovalerate and pivarate) were used as model prodrugs and the amounts excreted in urine were measured after percutaneous application. In vivo penetration profiles were then estimated by employing a deconvolution method and the penetration of acyclovir prodrugs was analyzed using a diffusion model. Subsequently, diffusion, partitioning and metabolic parameters were compared under in vitro and in vivo conditions., Results: Although total penetration amounts at the end of the experiment were similar for the three prodrugs, the ratio of intact prodrug to total penetration amount differed significantly. Moreover, the excretion and absorption profiles were also very different for each prodrug. Enzymatic hydrolysis rate constants calculated under in vivo conditions were considerably larger than those obtained in the skin homogenate and in vitro penetration experiments., Conclusions: The present skin diffusion/bioconversion model combined with computer analysis enables us to comprehensively account for diffusion, partitioning and metabolism during in vivo percutaneous absorption. Nevertheless, different enzymatic hydrolysis rate constants obtained under both in vivo and in vitro conditions demonstrate the difficulty of obtaining accurate values for in vivo enzymatic activity from related in vitro experiments.

A series of 5'-(O-acyl and O-benzoyl) derivatives of 5-iodo-2'-deoxyuridine (IDU) was synthesized by direct acylation of the parent nucleoside in a pyridine-N,N'-dimethylformamide mixture (1:1). Aqueous solubilities in phosphate buffer (pH 7.4), partition coefficients in 1-octanol/phosphate buffer (pH 7.4), plasma protein binding properties, and plasma reversion kinetics of these potential prodrugs were evaluated. The esters showed an expected increase in lipophilicity with a corresponding decrease in aqueous solubility relative to the parent compound. The association constants (Ka) with albumin also exhibited a good linear correlation with the lipophilicity of the compounds. However, the reversion rate constants in plasma varied with the steric and polar nature of the acyl or benzoyl substituent.

Mitomycin C-Dextran conjugates (MMC-D) were intravenously (iv) injected in mice bearing subcutaneous sarcoma 180. The tissue distribution was determined for three 14-C-labeled anionic conjugates (MMC-Dan) with molecular weights of 10, 70, and 500 kd and one cationic 70-kd 14C-conjugate (MMC-Dcat). The anionic conjugates were slowly cleared from the plasma, and their elimination rate decreased with increasing molecular weight. Radioactivity accumulated in liver, spleen, lymph nodes, and tumor but not in heart, lung, intestines, kidney, or muscle after iv injection of all types of 14C-MMC-Dan. In contrast, the cationic conjugate was rapidly cleared from the plasma and accumulated mostly in the liver and spleen, while tumor levels remained low. The antitumor effect of the 70-kd MMC-Dan, which afforded the highest tumor concentration, was superior to that of free MMC. Therefore, anionic mitomycin C-dextran conjugates with a high molecular weight may be useful for tumor targeting in cancer chemotherapy.

The utilization time (UT) for a solution of a prodrug that is rapidly and completely converted to drug in the blood may be longer than the time for 10% loss of the initial concentration. The UT for an intravenous prodrug solution is the period during which the total prodrug and drug concentration exceeds 90% of the initial concentration. The influence of the rate of prodrug degradation (knc), its conversion (kc) to drug, and the subsequent drug degradation (kh) on the UT of a stored solution was examined by simulating the prodrug and drug concentration-time courses. The ratio of the shelf life of a prodrug solution to that of the parent drug (UTratio) was calculated using a wide range of values for the three rate constants. Three-dimensional plots relating the UTratio to the kc, knc, and kh values provide a basis for making a priori assessments of kinetic requirements for designing a prodrug to increase storage time. A parenteral prodrug intended to increase storage time may have a larger overall rate of loss than the parent drug, but it must have a smaller degradation rate (knc less than kh) to be successful. The UT for an oral prodrug solution depends upon the bioavailability of the prodrug relative to the drug in addition to the values for knc, kc, and kh. Two ampicillin prodrugs were used as models to calculate actual UTratio versus pH profiles. Intravenous solutions showed modest gains in the UTratio in the acid region, whereas oral solutions reached a UTratio as high as 22 by combining favorable rate constants with increased bioavailability.(ABSTRACT TRUNCATED AT 250 WORDS)