A Comparison of Oral and Rectal Absorption of L-Dopa Esters in Rats and Mice

Short-chain alkyl esters of L-dopa were administered to rats and mice via oral and rectal routes. Plasma L-dopa esters and L-dopa were determined in the systemic and portal circulation by HPLC. A comparison of isopropyl, butyl, and 4-hydroxybutyl esters of L-dopa demonstrated significantly higher levels of the esters in both systemic and portal blood samples following rectal administration than following oral administration. In most cases, oral administration resulted in nondetectable (<0.01 µg/ml) levels of the esters in plasma. Correspondingly, the plasma levels of L-dopa itself were consistently higher following rectal administration. At very high oral doses (500 mg L-dopa equivalents/kg body weight), systemic plasma levels of the butyl ester could be detected (1.25 µg/ml at 10 min), which might indicate saturation of the esterase activity of the small intestine. These studies indicate that the systemic availability of L-dopa from short-chain alkyl esters of L-dopa may be best optimized by rectal administration, which avoids the relatively high esterase activity characteristic of the small intestine.     

N-(Acyloxyalkoxycarbonyl) derivatives as potential prodrugs of amines. II. esterase-catalysed release of parent amines from model prodrugs

N-(Acetoxyethoxycarbonyl) derivatives of primary amines released a major fraction of the parent amine in the desired free form in plasma but a significant fraction of the undesired N-acetylated parent amine was also produced. The fraction of the parent amines released from the carbamate derivatives of the primary amines was greater in human plasma than in pH 7.4 buffer. In human plasma, the N-(acetoxyethoxycarbonyl) derivative of a secondary amine released the parent amine in a quantitative manner at a rate higher than that observed in pH 7.4 buffer. Experimental results suggested that the observed catalysis of the release of the parent amines from N-(acetoxyethoxycarbonyl) derivatives of primary and secondary amines was due to participation by plasma esterases. The data suggested that N-(acetoxyethoxycarbonyl) derivatives are well suited for use as prodrugs of secondary amines. Their utility as prodrugs of primary amines is more problematic and cannot be predicted prior to in-vivo studies for the individual compound.     

Cation exchange contribution to the retention of specific quaternary ammonium compounds in reversed-phase high-performance liquid chromatography

The influence of electrolytes on the retention of organic cationic solutes in reversed-phase high-performance liquid chromatography (RP-HPLC) has been investigated. The effects of the nature and concentration of electrolytes and mobile phase pH on the retention of two model quaternary ammonium compounds were studied on mu-Bondapak C18 stationary phase with aqueous methanolic eluents. The nature and concentration of inorganic cations added to the mobile phase modified the retention of the solutes. The counter anion of the added electrolyte did not perceptibly influence solute retention at constant mobile phase pH, although it did significantly influence solute retention when the electrolytes were added to unbuffered mobile phases. The retention data are consistent with the inclusion of an ion exchange contribution to the retention of cationic solutes in the systems investigated.     

Rational development of a soluble prodrug of a cytotoxic nucleoside: preparation and properties of arabinosyladenine 5'-formate.

The 5'-O-formate ester of arabinosyladenine was synthesized and shown to be suitable as a water-soluble prodrug, being at least 60 times more soluble than the parent cytotoxic nucleoside. This increased solubility was ascribed to a decrease in intermolecular interaction in the crystalline state, as evidenced by an similar 90 degrees lower melting point for the ester relative to the parent compound. The prodrug reverted to the parent compound in aqueous solution, its pH-rate profile being V-shaped with maximum stability at a pH similar 4.2, corresponding to a half-life of about 10 days. The rate of hydrolysis of the prodrug at 37degrees in 91% human serum and 91% whole blood was studied. At an initial concentration of 0.4 mg of prodrug/ml of 91% whole blood, reversion to arabinosyladenine appeared to be essentially complete in about 15 min. The prodrug did not appear to be subject to enzymatic deamination. This feature, together with the good solubility of the prodrug, makes possible the effective formulation of arabinosyladenine for intravenous purposes. The rationale involved in the general design of a prodrug and the specific considerations necessitated in the case of adenine arabinoside are discussed.     

Stability of propranolol hydrochloride suspension compounded from tablets

The stability of a propranolol hydrochloride suspension compounded from commercially available tablets was studied. Propranolol hydrochloride 10-mg tablets were triturated to a powder and incorporated into a commercially available suspension vehicle to yield a suspension with a theoretical propranolol hydrochloride concentration of 1 mg/mL. The suspension was divided into portions and stored in amber glass bottles at either room (25 degrees C) or refrigerated (2 degrees C) temperature for four months. The concentration of propranolol hydrochloride in the samples was determined by a stability-indicating, high-performance liquid chromatographic (HPLC) assay at 0, 30, 60, 90, and 120 days. Also at these times, the pH of the samples was measured, and the samples were inspected visually for evidence of microbial growth and ease of resuspension. The concentration of propranolol hydrochloride in the samples remained within 90% of the initial concentration throughout the study period. No important changes in the pH of the samples and no visible evidence of microbial growth were noted. This extemporaneous suspension of propranolol hydrochloride compounded from commercially available tablets is stable for at least four months when stored at room or refrigerated temperature.     

Complexation in the retention of benzoic acids on a bonded xanthine HPLC stationary phase

The retention of a number of benzoic acids was determined using a bonded xanthine stationary phase (XSP). Retention of benzoate on XSP was studied as a function of pH and organic modifier composition of the mobile phase. The measured retention for 10 substituted benzoic acids was correlated with the complexation constants previously reported for these compounds with theophylline.     

Complexation in formulation of parenteral solutions: solubilization of the cytotoxic agent hexamethylmelamine by complexation with gentisic acid species.

The apparent solubility of hexamethylmelamine in aqueous solutions suitable for intravenous use was increased by complexation with gentisic acid. Studies were carried out in the pH 0-8 range. Unprotonated hexamethylmelamine did not form complexes with the gentisate ion, while the hexamethylmelammonium ion appeared to form several different complexes with both the gentidate ion and gentisic acid. Two different solid complexes were isolated and characterized. The solubility increases observed at pH 3.5-5.0 are described by mathematical relationships involving the stability constants of some postulated complex species. From these results, sultable formulations for use as parenteral solutions are proposed. The increase in the apparent aqueous solubility of hexamethylmelamine in such formulations may range from five- to 90-fold, depending upon the pH and total gentisateion concentrations.     

Analysis of the prodrug 7-acetylacroninium perchlorate in presence of the parent compound acronine

Analysis of acronine and the prodrug acetylacroninium perchlorate in parenteral solutions is described. The unstable prodrug reacts quantitatively with the nucleophilic agent aniline by an unusual mechanism to form a phenylimino derivative of acronine. This derivative and acronine itself were determined by a spectrophotometric two-component method.