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Biomedical subjects

H Bundgaard

Publications and source records attributed to H Bundgaard.

At least 91 records · Page 5Linked to original sources
PubMed1989

Kinetics of the acid-catalyzed hydrolysis of cimetidine.

The kinetics of hydrolysis of cimetidine was studied in 0.01-1 M hydrochloric acid solutions (pH 0.15-2.15) at 37 degrees C. The hydrolytic cleavage of the cyanoguanidino group in cimetidine to give a guanylurea derivative was found to proceed quantitatively, as evidenced by HPLC analysis. The rate of hydrolysis was subject to specific acid catalysis, the specific hydrogen ion catalytic rate constant being 3.6 X 10(-3) M-1 min-1 at 37 degrees C and mu = 0.5. Increased ionic strength accelerated the rate of hydrolysis. The possible significance of the acid-catalyzed hydrolysis for the stability of cimetidine during its transit through the stomach after peroral administration was assessed. It was estimated that in the gastric pH range 1-2 and with a gastric emptying half-time of 50 min, only 0.3-2.5% of an ingested dose would be hydrolyzed in the stomach.

Biological Availability↗
PubMed1988

Glycolamide esters as biolabile prodrugs of carboxylic acid agents: synthesis, stability, bioconversion, and physicochemical properties.

Benzoic acid esters of various substituted 2-hydroxyacetamides (glycolamides) were found to be hydrolyzed extremely rapidly in human plasma solutions, the half-lives of hydrolysis being less than 5 s in 50% plasma solutions for some N,N-disubstituted glycolamide esters. The rapid rate of hydrolysis could be largely attributed to cholinesterase (also called pseudocholinesterase) present in plasma. From a study of a variety of substituted glycolamide esters and structurally related esters, the most prominent structural requirement needed for a rapid rate of hydrolysis was found to be the glycolamide ester structure combined with the presence of two substituents on the amide nitrogen atom. A structural similarity of such esters with benzoylcholine, a good substrate for cholinesterase, was put forward. Esters of N,N-disubstituted glycolamides are suggested to be a useful biolabile prodrug type for several carboxylic acid agents. The esters combine a high susceptibility to undergo enzymatic hydrolysis in plasma with a high stability in aqueous solution. Furthermore, as demonstrated with the benzoic acid model esters, it is feasible to obtain ester derivatives with almost any desired water solubility or lipophilicity with retainment of marked lability to enzymatic hydrolysis.

Biotransformation↗
PubMed1988

Relative effectiveness of prodrug and viscous solution approaches in maximizing the ratio of ocular to systemic absorption of topically applied timolol.

The effectiveness of the prodrug approach in maximizing the ratio of ocular to systemic absorption of topically applied timolol was compared with that based on viscous solutions. The pigmented rabbit was the experimental animal. o-Butyryl timolol, a lipophilic ester prodrug of timolol, was found to be twice as effective as hyaluronic acid and poly(vinyl alcohol) solutions in enhancing the ocular absorption of timolol. In addition, it was slightly more effective than retaining the instilled dose in the conjunctival sac for 240 min via nasolacrimal blockade. On the other hand, due to its inability to minimize contact of the instilled dose with the nasal mucosa, o-butyryl timolol was less capable than the viscous solutions in reducing systemic drug absorption. But this could be corrected by reducing the instilled solution volume from 25- to 5 microliter, resulting in a nine-fold reduction in plasma timolol levels while still providing the same amount of drug in the aqueous humor as a five times higher dose of timolol. The net result was a 15-fold improvement in the ratio of ocular to systemic drug absorption, which was also achieved upon retaining the instilled dose in the conjunctival sac for 240 min. It thus appears that the approach based on improved corneal absorption would be as effective as that based on improved retention in the conjunctival sac in maximizing the ratio of ocular to systemic drug absorption, so long as a smaller instilled dose volume of the prodrug is used.

Administration, Topical↗
PubMed1988

Influence of corneal epithelial integrity on the penetration of timolol prodrugs.

The interplay of corneal epithelial integrity and prodrug lipophilicity in the corneal penetration of a homologous series of timolol prodrugs was studied. A reversed phase HPLC procedure was used to assay for timolol and its prodrugs. The optimal distribution coefficient for corneal penetration on a logarithmic basis was found to be 2.5, and for two prodrugs of equal lipophilicity the enzymatically labile one was better absorbed. The corneal permeability coefficient of O-acetyl, propionyl, and butyryl timolol was unaffected by deepithelizing the cornea, whereas that of the other prodrugs was reduced. This suggests that these three prodrugs diffused across the corneal epithelium proper as readily as across its basement membrane, which was not removed by the deepithelizing procedure. In contrast to the in vitro results, deepithelizing the cornea did not affect the aqueous humor concentration of timolol at 20 min afforded by any of the prodrugs except the O-propionyl and octanoyl esters. This suggests that factors other than corneal penetration exerted a more important role in affecting the aqueous humor drug concentration when the cornea was deepithelized.

Animals↗
PubMed1988

Facile plasma-catalysed degradation of penicillin alkyl esters but with no liberation of the parent penicillin.

The methyl ester and some glycolamide esters of benzylpenicillin and ampicillin were shown to be rapidly degraded by human plasma at 37 degrees C with no parent penicillin being produced. The plasma-catalysed degradation which was also observed in rat plasma proceeds most likely through hydrolytic cleavage of the beta-lactam bonds of the penicillin esters and is suggested to be due to the presence of an ester-specific beta-lactamase in plasma. The results show that the failure of simple alkyl esters of penicillins to function as prodrugs is not due to a high enzymatic stability of the esters, as widely believed, but rather to a pronounced susceptibility to undergo hydrolytic cleavage of their beta-lactam ring in-vivo. Since double ester prodrugs of penicillins, such as the pivaloyloxymethyl ester of ampicillin, are readily hydrolysed in plasma to yield the parent penicillin although at a rate lower than e.g. that of inactivation of a simple methyl ester, the plasma enzyme apparently attacking the beta-lactam bond of penicillin esters appears to have a high degree of specificity for the ester structure.

Biotransformation↗
PubMed1988

Ocular and cardiac beta-antagonism by timolol prodrugs, timolol and levobunolol.

Topically applied O-butyryl timolol, O-pivaloyl timolol and levobunolol (0.25 micrograms) antagonized isoproterenol-induced ocular hypotension for 8 hrs whereas timolol (0.25 micrograms) was shorter acting (4 hrs). Timolol (25 micrograms) produced greater antagonism of isoproterenol-induced tachycardia than did O-butyryl and O-pivaloyl timolol (25 micrograms). These results suggest that, at similar doses, O-butyryl and O-pivaloyl timolol produce high concentrations of timolol in ocular tissues and undergo redistribution more slowly into the systemic circulation than does topical timolol. Under certain circumstances, prodrugs may provide a mechanism for increasing selectivity and extending the duration of action in the target organ as well as decreasing systemic effects.

Adrenergic beta-Antagonists↗
PubMed1988

Low dose O-butyryl timolol improves the therapeutic index of timolol in the pigmented rabbit.

The degree of enhancement in the ocular absorption of timolol afforded by its O-butyryl prodrug and the possibility of reducing its systemic absorption through a proportional reduction in its instilled dose were investigated in the pigmented rabbit. A reversed phase HPLC procedure was used to assay for timolol and O-butyryl timolol in the aqueous humor and plasma over 120 min post-instillation of 25 microliter of drug solutions. We found that the ocular absorption of the O-butyryl prodrug of timolol from a 15 mM solution was 5.5 times greater than that of the parent drug while the systemic absorption was comparable. When a lower concentration of the prodrug (3.75 mM) was used the therapeutic index as assessed by the ratio of aqueous humor to plasma concentrations seemed to improve fifteenfold. Therefore, it is possible to significantly reduce the systemic absorption of timolol without reducing its ocular absorption by using a low dose of its O-butyryl prodrug.

Absorption↗
PubMed1987

Improved corneal penetration of timolol by prodrugs as a means to reduce systemic drug load.

A major problem in the use of timolol in glaucoma therapy is its relatively high incidence of cardiovascular and respiratory side effects. This report presents preliminary evidence for the feasibility of a prodrug approach to minimize systemic absorption of timolol using a reduced topical dose made possible by improved corneal drug penetration. The results indicate that the O-acetyl, propionyl, butyryl, and pivalyl ester prodrugs of timolol were virtually completely hydrolyzed between 30 and 150 min when incubated with plasma, aqueous humor, and ocular tissue homogenates of pigmented rabbits. Moreover, the in vitro corneal penetration of all but the O-pivalyl prodrug was 2-3 times higher than timolol. This was accompanied by a four- to sixfold increase in aqueous humor concentration at 5 and 30 min post-instillation of 15 mM solutions, although the plasma timolol concentration at the same time points was either unaltered or slightly reduced. Collectively, these preliminary findings suggest that at least a twofold reduction in the topical dose of timolol is possible by using prodrugs, thereby reducing timolol concentration in the systemic circulation and possibly the incidence of cardiovascular and respiratory side effects.

Animals↗
PubMed1986

Pilocarpine prodrugs I. Synthesis, physicochemical properties and kinetics of lactonization of pilocarpic acid esters.

Various alkyl and aralkyl esters of pilocarpic acid were synthesized and evaluated as prodrug forms for pilocarpine with the purpose of improving the ocular bioavailability of pilocarpine through increased corneal membrane permeability. The esters were found to undergo a quantitative cyclization to pilocarpine in aqueous solution of pH 3.5-10, the rate of cyclization being a function of the polar and steric effects within the alcohol portion of the esters. The rates of lactonization increased proportionally with the hydroxide ion activity over the pH range studied which is in accord with a reaction mechanism involving intramolecular nucleophilic attack of alkoxide ion on the ester carbonyl moiety. At pH 7.4 and 37 degrees C, half-times of lactonization ranging from 30 min (p-chlorobenzyl ester) to 1105 min (n-hexyl ester) were observed for the various esters. The esters are markedly more lipophilic than pilocarpine. The results suggested that the pilocarpic acid esters may be potentially useful prodrugs, especially when further derivatized to give in vitro stable pilocarpic acid diesters.

Chemical Phenomena↗
PubMed1986

Prodrugs of 5-fluorouracil. V. 1-Alkoxycarbonyl derivatives as potential prodrug forms for improved rectal or oral delivery of 5-fluorouracil.

The hydrolysis and physicochemical properties of seven 1-alkoxycarbonyl derivatives of 5-fluorouracil were studied to assess their potential as prodrugs with the aim of enhancing the delivery characteristics of the parent drug. All derivatives were hydrolyzed to quantitatively yield 5-fluorouracil. The pH-rate profiles for the hydrolysis were measured. The rates of hydrolysis were markedly accelerated in the presence of plasma, affording half-lives of hydrolysis less than 4 min in 80% human plasma. The derivatives were more lipophilic than 5-fluorouracil but the aqueous solubility was only slightly reduced or, for one derivative, even greater than that of 5-fluorouracil. A preliminary absorption study in rabbits showed an absolute bioavailability of 5-fluorouracil of 100% following rectal administration of 1-(butoxycarbonyl)-5-fluorouracil as compared with no absorption following administration of 5-fluorouracil itself. The potential utility of the prodrug derivatives to enhance the oral and/or rectal delivery of the parent drug is suggested.

Animals↗
PubMed1986

Pilocarpine prodrugs. II. Synthesis, stability, bioconversion, and physicochemical properties of sequentially labile pilocarpine acid diesters.

Various novel diesters of pilocarpic acid were synthesized and evaluated as prodrug forms for pilocarpine with the aim of improving the ocular delivery characteristics of the drug. The pilocarpic acid monoesters previously studied cyclized spontaneously to pilocarpine in aqueous solution and although they showed enhanced corneal permeability when compared with pilocarpine these monoesters suffered from poor solution stability. The present study shows that this problem can be totally overcome by blocking the free hydroxyl group in the monoesters. Diesters of pilocarpic acid were obtained by esterification of this group. Such compounds were found to possess a high stability in aqueous solution (shelf lives of more than 5 years at 20 degrees C were estimated) but at the same time were readily converted to pilocarpine under conditions simulating those occurring in vivo through a sequential process involving enzymatic hydrolysis of the O-acyl bond followed by spontaneous lactonization of the intermediate pilocarpic acid monoester. Rate data are given for the conversion of the diesters in human plasma and in various rabbit eye homogenates. The pH-solubility profile was derived for a diester and lipophilicity parameters were determined for the compounds. All diesters were markedly more lipophilic than pilocarpine and the corresponding pilocarpic acid monoesters. The results suggest that pilocarpic acid diesters may be potentially useful pilocarpine prodrugs as they combine a high solution stability with an adequate rate of conversion to pilocarpine under in vivo conditions.

Animals↗