Prodrug Of Ampicillin Research Articles

Polymeric prodrugs of ampicillin as antibacterial coatings

A novel ampicillin prodrug containing two carboxylic acid functionalities was synthesized by reacting ampicillin with acyl chloride in the presence of base. This prodrug was subsequently converted into a poly(anhydride-amide) via solution polymerization. The polymer, which chemically incorporates the ampicillin prodrug into the polymeric backbone, was developed as a film to prevent infections associated with medical devices by controlled, localized release of antimicrobials. The robust polymer coatings exhibiting strong adhesion to stainless steel were produced under elevated temperature and reduced pressure. The in vitro hydrolytic degradation of the polymer into the ampicillin prodrug was measured and the antibacterial activity of polymer-derived coatings was examined using a Gram-positive bacterium, Staphylococcus aureus. Furthermore, the polymer cytotoxicity was screened using fibroblasts. The ampicillin prodrug demonstrated antibacterial activity and the polymer demonstrated no cytotoxic effects on fibroblasts. Based on these results, the biodegradation of the antimicrobial-based poly(anhydride-amide) into the prodrug displays substantial promise as an implant or implant coating to reduce device failure resulting from bacterial infections.

Kinetic assessment of luminal degradation of orally effective prodrugs for rational drug development

Although prodrugging (prodrug derivatization) is a powerful technique for improving the pharmacokinetic characteristics of drugs, the intestinal pharmacokinetics of prodrugs has yet to be elucidated fully. A previous article reported the kinetic requirement of prodrugs to overcome membrane barriers. In the present article, the luminal degradation of prodrugs was kinetically assessed to understand crucial factors in the intestinal absorption of prodrugs and to show a rational development procedure. A kinetic model equation involving luminal degradation clearance (CLdeg) was derived, and CLdeg was estimated according to the equation with in vitro and in vivo reported data of two kinds of ampicillin prodrugs (lenampicillin and pivampicillin) and one acyclovir prodrug (valacyclovir). For lenampicillin ((2,2-dimethyl-1-oxopropoxy)methyl ester derivative), CLdeg was approximately 1.7 times as large as absorption clearance (CLabs), whereas for pivampicillin ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester derivative), CLdeg was approximately one tenth of CLabs. For valacyclovir (acyclovir prodrug), CLdeg was negligible. These results indicate that not only membrane permeability but also luminal stability should be assessed for the rational development of orally effective prodrugs, and that luminal stabilization can improve the intestinal absorption of prodrugs. A procedure was proposed to develop orally effective prodrugs considered for luminal degradation as well as membrane permeability. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1078–1086, 2010

Simultaneous HPLC Assay of Lenampicillin (Ampicillin Prodrug), Ampicillin, and Marker Compound for High‐Throughput in Vitro Assessment of Intestinal Absorption and Metabolism Using Caco‐2 Cells

A high performance liquid chromatographic assay method was established to simultaneously determine lenampicillin (ampicillin prodrug), ampicillin, and an absorption marker compound (antipyrine) for the high‐throughput in vitro assessment of intestinal absorption and metabolism using Caco‐2 cells. These compounds were determined using an octyl (C8) column, mobile phase consisting of 37% methanol and 10 mM NaH2PO4 in water (pH 4.5) at a flow rate of 1.5 mL/min, and a UV‐detector (200 nm). For lenampicillin, the slope and its S.D. of a typical calibration line going through the coordinate origin (peak area ratio of lenampicillin to internal standard versus lenampicillin concentration from 0.5 µM to 0.5 mM) were 2.91×10−3 and 1.83×10−5, respectively. The correlation coefficient (r) of the calibration line in the inter‐assays of lenampicillin was 0.9994 (coefficient of variation=0.04%). For ampicillin, the slope and its S.D. of a typical calibration line going through the coordinate origin (peak area ratio of ampicillin to internal standard versus ampicillin concentration from 0.5 µM to 0.5 mM) were 2.28×10−3 and 1.04×10−5, respectively. The correlation coefficient (r) of the calibration line in the inter‐assays of ampicillin was 0.9999 (coefficient of variation=0.01%). Lenampicillin absorption and metabolism to ampicillin were shown by this assay method.

Intracellular accumulation and activity of ampicillin used as free drug and as its phthalimidomethyl or pivaloyloxymethyl ester (pivampicillin) against Listeria monocytogenes in J774 macrophages.

To determine the intracellular accumulation in a macrophage cell line of ampicillin and ampicillin esters, and to measure their activity against intracellular Listeria monocytogenes. Quantitative evaluation of the activity of ampicillin, phthalimidomethylampicillin (PIMA) or pivaloyloxymethylampicillin (PIVA) against intracellular L. monocytogenes, and direct measurement of cellular ampicillin concentration in J774 macrophages. Ampicillin, PIMA and PIVA caused a 0.5 log decrease in cell-associated cfu within 5 h when used at an extracellular concentration of 3.6 microM [10 x MIC of ampicillin (1.25 mg/L); 1.83 mg/L for PIMA and 1.67 mg/L for PIVA]. Addition of beta-lactamase in the extracellular milieu abolished the activity of ampicillin and of PIMA but not that of PIVA. At low extracellular concentrations [0.5 x MIC ampicillin (62.5 microg/L); equimolar concentrations for PIMA (91.5 microg/L) and PIVA (83.5 microg/L)], ampicillin and PIMA lost all activity (compared with controls), but PIVA remained as active as at the higher concentration. Incubation of cells with PIVA at the low concentration (83.5 microg/L) for 20 h caused a 2 log reduction of cfu if the medium was changed every 5 h (to compensate for the degradation of extracellular PIVA). Incubation of cells with PIVA allowed for a marked (four- to 25-fold) cell accumulation of ampicillin, whereas no ampicillin accumulation was seen for cells incubated with ampicillin or with PIMA. This is the first demonstration that PIVA (a prodrug of ampicillin) can be used to promote ampicillin cellular accumulation and, thereby to increase ampicillin intracellular activity. PIVA could be useful for control of the intracellular multiplication of L. monocytogenes.

Analysis of an ampicillin propyl ester prodrug which inhibits the growth of Escherichia coli.

An ampicillin prodrug was synthesized by utilizing the chemical reaction of ampicillin with diazopropane (CH(3)CH(2)CHN(2)) in an organic solvent. The result is esterification of the carboxylic acid functional group. The ampicillin prodrug is a solid that forms yellow crystals which are soluble in water and LB agarose media. The ampicillin prodrug was stable for more than 10 weeks when stored at < or = 0.0 degrees C. The prodrug has reduced hydrogen-bonding capability compared with the unmodified structure of ampicillin. Evaluation of the logP parameter (the octanol/water partition coefficient) indicates that the ampicillin prodrug (logP=1.773) has increased lipophilic characteristics relative to the unmodified ampicillin structure (logP=1.06). The lipophilic substituent constant for the esterification of the carboxylic acid is 0.713, a positive value which indicates that the substituent has a lipophilic nature. The ampicillin prodrug was solubilized into LB agarose media at a concentration of 0.228 mg/ml, and was found to induce 100% growth inhibition of an ampicillin-susceptible and streptomycin-resistant Escherichia coli strain (designated DH1), and induced greater than 30% growth inhibition of an ampicillin-resistant E. coli strain (designated PKK). Synthesis of this prodrug utilizing a diazoalkane was highly efficient, with no undesirable by-products being formed.

Synthesis of 1,1-dioxopenicillanoyloxymethyl 6-[ d-α-(benzylideneaminophenylacetamido)]penicillanate and analogs. New intermediates in the preparation of sultamicillin

The synthesis of benzylidene imines of sultamicillin and analogs 1 is described. These new compounds showed high stability and were prepared under very mild conditions and high yields. Furthermore, they are convenient starting materials for the preparation of sultamicillin 5 (important prodrug of ampicillin and sulbactam) as its base form, by deprotection of the amino group with Girard reagents.

Distribution of penicillins into subcutaneous tissue chambers in ponies.

The distribution of penicillins into a tissue chamber implanted subcutaneously in ponies was studied. Ampicillin sodium (equivalent to 15 mg/kg ampicillin) was administered intravenously. Pivampicillin, a prodrug of ampicillin, was administered by nasogastric tube to fed ponies at a dose of 19.9 mg/kg (equivalent to 15 mg/kg ampicillin). Procaine penicillin G was administered intramuscularly at a dose of 12 mg/kg (equivalent to 12000 IU/kg). Six ponies were used for each medication. Antibiotic concentrations in plasma and tissue chamber fluid (TCF) were measured for 24 h after administration. Mean peak concentrations of ampicillin in TCF were 7.3 micrograms/mL, reached at 1.7 h, and 1.3 micrograms/mL, reached at 2.7 h, after administration of ampicillin sodium and pivampicillin respectively. The mean peak concentration of penicillin G of 0.3 microgram/mL was reached 12.3 h after administration of procaine penicillin G. Concentrations in TCF remained above the minimum inhibitory concentration of Streptococcus zooepidemicus for the proposed dosing intervals of 8, 12 and 24 h for ampicillin sodium, pivampicillin and procaine penicillin G respectively.

Ampicillin and its congener prodrugs in the horse

Ampicillin is an antibiotic commonly administered to horses by both the intramuscular (i.m.) and the intravenous (i.v.) route. Its physicochemical properties restrict its absorption after oral administration and explain its rapid elimination from the body. To prolong the effects of ampicillin in the horse, attempts have been made to alter its elimination and absorption rates. The alteration of urinary pH did not change the plasma disposition of the antibiotic but when probenecid was administered concurrently with ampicillin, a significant reduction of total body clearance was achieved. Ampicillin may also be maintained in the equine body, for a prolonged period of time when administered as an i.v. infusion. However, the practical difficulties associated with this route of administration and the limited potential advantage over conventional routes such as i.m. injection restrict its application to the critically ill animal and the perioperative period. When bacampicillin and pivampicillin (two ampicillin prodrugs) were administered to horses, high oral bioavailability was obtained, and the use of prodrugs commands the need for further investigation. The use of ampicillin might be limited in the future as an increase in the number of resistant equine bacterial strains emerge and it may be prudent to restrict its use according to the principles of good clinical pharmacological practice.

Pharmacokinetics of bacampicillin using a compartment model with zero-order absorption.

The pharmacokinetics of bacampicillin, a prodrug of ampicillin which is absorbed from the gastrointestinal tract, were studied in 10 healthy male volunteers after administration of 1,200 mg in a single oral dose. The pharmacokinetic analysis was carried out by applying a single-compartment kinetic model with zero-order absorption. The apparent duration of absorption (T) was about 1 h for all subjects. The peak plasma concentrations (Cmax) were 17.89 +/- 1.82 micrograms/ml, and the mean plasma half-life during beta-phase was 1.17 +/- 0.14 h. The area under the curve was 41.22 +/- 5.29 micrograms.h/ml. The mean urinary recovery during 24 h amounted to 76.4 +/- 3.65% of the dose.

Potential improvement in shelf life using the prodrug approach. II. A systematic examination of kinetic requirements.

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)

Bioactive polymers, 51. Synthesis and characterization of a macromolecular prodrug of ampicillin

AbstractThe coupling reaction of ampicillin with the polysaccharide xanthane in DMSO, using dicyclohexylcarbodiimide as activator, was studied. To find the conditions for maximum yield a regression equation was established, describing the dependence of the yield of coupling product on the reaction parameters (drug/support mole ratio, activator/support mole ratio and duration), starting from an experimental, centrated rotable complex, second order program. The coupling product was spectroscopically characterized and the in vitro release rate of ampicillin in a weakly basic medium was established along with the determination of its antimicrobiological activity.

Hydrolysis of pivampicillin in buffer and plasma solutions. Formation of a 4-imidazolidinone from ampicillin and formaldehyde

The degradation of pivampicillin, an ampicillin prodrug, was studied in phosphate buffer solutions of pH 7.40 and in human plasma solutions. The degradation course of pivampicillin was found to involve a quantitative hydrolysis of the pivaloyl ester moiety followed by a reversible reaction between the initial hydrolysis products, ampicillin and formaldehyde, to yield a 4-imidazolidinone derivative of ampicillin. This secondary reaction was shown to account for previously reported findings of decreased yields of both ampicillin and formaldehyde upon the enzymatic and non-enzymatic degradation of pivampicillin.

ChemInform Abstract: STUDIES ON PRODRUGS. III. A CONVENIENT AND PRACTICAL PREPARATION OF AMPICILLIN PRODRUGS

AbstractDie aus (Ia) entstehende geschützte Penicillansäure (Ib) wird entsprechend dem Formelschema zu den Estern (II) umgesetzt, die mit dem Aminosäurechlorid (III) zu den Ampicillinen (IV) reagieren.

Linear systems analysis and moment analysis in the evaluation of bacampicillin bioavailability from microcapsule suspensions.

Linear systems analysis, i.e., numerical convolution/deconvolution, and moment analysis have been performed on data obtained from microcapsules containing the ampicillin prodrug bacampicillin hydrochloride. Three batches with different in vitro dissolution rates were scrutinized. From the results, it is concluded that numerical convolution/deconvolution is a valuable tool for predicting bacampicillin bioavailability. However, it must be emphasized that the selection of an appropriate time module is important for predicting an in vivo response that reflects the actual situation. This was verified by comparing the predicted plasma response values with the values obtained in a bioavailability study in healthy volunteers. A correlation between mean residence time in vivo and mean dissolution time in vitro was also found which thus demonstrates the usefulness of moment analysis for obtaining an in vivo-in vitro relationship. This relationship was compared to a correlation found between the mean dissolution time in vitro and the empirical maximum plasma concentration of bacampicillin.

Correlation Between the Bioavailability of Microencapsulated Bacampicillin Hydrochloride in Suspension and In Vitro Microcapsule Dissolution

The relative bioavailability of microencapsulated bacampicillin hydrochloride in suspension was correlated with the in vitro dissolution half-lives of the microcapsules. Simultaneously, a sensory evaluation was performed to evaluate the taste acceptability of the suspension. The in vitro dissolution half-life is directly related to the coating thickness of the microcapsules. The four suspensions of bacampicillin hydrochloride, containing microcapsules with different coating thickness, were given as single 400-mg oral doses to 12 healthy volunteers after overnight fasting using a crossover design with balanced sequences. Bacampicillin is a prodrug of ampicillin, the concentration of which was determined in plasma and urine by bioassay. There were significant inverse linear relationships between the dissolution half-life and plasma peak concentration, area under the curve, and urinary recovery. The terminal exponential disposition phases of the curves were similar for all four suspensions. There was a significant direct linear relationship between the dissolution half-life and overall taste and bitterness. The results show that the mean bioavailability of bacampicillin hydrochloride from a microcapsule suspension can be predicted from an in vitro dissolution half-life. The results also suggest that bacampicillin hydrochloride can be given in a suspension with sufficient microcapsule film thickness to reduce the bitter taste of the drug and still retain adequate bioavailability.

Studies on prodrugs. III. A convenient and practical preparation of ampicillin prodrugs.

In order to prepare ampicillin prodrugs conveniently for practical use, a new synthetic method for 6β-aminopenicillanic acid (6-APA) esters as key intermediates of various ampicillin prodrugs has been developed. Acylation of 6-APA esters to ampicillin esters was achieved in good yields by using phenylglycyl chloride hydrochloride in dichloromethane in the presence of sodium bicarbonate and amide, or ammonium bicarbonate alone. KBT-1585, bacampicillin, talampicillin and pivampicillin have been obtained in good yields by this procedure.

Studies on prodrugs. I. Preparation and characterization of acyloxyallylester of ampicillin.

In order to investigate a new type of promoiety for ampicillin prodrugs, acyloxyallyl esters were prepared and their oral absorbabilities, stabilities and hydrolyzabilities to parent ampicillin were studied. As starting materials for (3-phthalidylidene)ethyl esters, ethylidenephthalide and its derivatives were regiospecifically prepared by a new method using the Wittig reaction. (3-Phthalidylidene)ethyl esters (14a-c) given orally were well absorbed, but (thiophthalidylidene)ethyl ester (14d) and (isocoumarin-4-yl)methyl ester (14e) were poorly absorbed.

Biopharmaceutical study on the oral and rectal administrations of enamine prodrugs of amino acid-like beta-lactam antibiotics in rabbits.

Enamine derivatives of ampicillin, amoxicillin and cephalexin were prepared by reacting the drugs with ethyl acetoacetate under mild conditions. The enamine structures of these compounds were determined by measurements of the nuclear magnetic resonance (NMR) spectra. The compounds were easily hydrolyzed in vitro in aqueous solution and the rate accelerated as the pH was lowered. The determination of Rf and rate of migration of the enamine derivatives showed that the enamine derivatives were more lipophilic than the corresponding parent drugs. The bioavailabilities of these prodrugs were studied following oral and rectal administrations in rabbits. The bioavailabilities of the parent antibiotics were not improved by the oral administration of the corresponding enamine prodrugs. However, the bioavailabilities of ampicillin and amoxicillin were markedly improved by rectal administration of the corresponding enamine prodrugs. The improved bioavailabilities exceeded those of the parent drugs following oral administration in rabbits. The enamine prodrug of ampicillin was found to promote the rectal absorption of ampicillin upon coadministration of these two drugs. Thus, enamine derivatives of amino acid-like β-lactam antibiotics appear to be interesting candidates for possible clinical use as prodrugs for rectal administration.

Lower respiratory tract infections treated with bacampicillin: a dose comparison.

In an open multicentre study of bacampicillin (Penglobe), a new orally well absorb ed prodrug of ampicillin, 516 patients with acute exacerbations of chronic bronchitis or pneumonia were treated by a group of Belgian pneumologists or internists. Bacampicillin was given in a dosage regimen of 400 mg or 800 mg three times daily. In patients with acute exacerbations of chronic bronchitis the clinical success rate was high, over 95% in both groups. An improvement in the sputum purulence score was seen in 93% of the patients with an initially purulent sputum and 69% had a normal mucoid sputum at follow-up. The clinical success rate in patients with pneumonia was also similar in both dosage groups with success rates over 96%. The total number of patients with adverse reactions was not more than 5-4%, of which the majority were considered mild or moderate. Each type of side-effect occurred in a frequency of 1-2% or less. There were no differences between the two dosage regiments as regards the frequency of side-effects indicates a remarkably good tolerance of bacampicillin also with the higher dosage.