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R E Notari

Publications and source records attributed to R E Notari.

At least 37 records · Page 2Linked to original sources
PubMed1984

Theoretical basis for the detection of general-base catalysis in the presence of predominating hydroxide catalysis.

The detection of general-base catalysis in the presence of predominating specific-base catalysis in aqueous buffer solutions is examined for various relationships between k0cat and k0OH, the bimolecular rate constants for general-base and hydroxide-ion attack. The three experimental variables that affect the detection of buffer-base catalysis are the type of buffer, conjugate-acid concentration, and ionic strength. Various buffers used in pharmaceutical kinetic studies are considered, and it is concluded that buffers with high Ka values favor detection. Additionally, high conjugate-acid concentrations and ionic strengths appear to optimize the detection of general-base catalysis.

Alkalies↗
PubMed1984

Pharmacokinetic prodrug modeling: in vitro and in vivo kinetics and mechanisms of ancitabine bioconversion to cytarabine.

Conversion rates of the prodrug ancitabine to the antileukemic cytarabine have been measured in vivo (rabbits) and in vitro (in the presence of rabbit blood and human red blood cells, blood, and plasma) using HPLC analyses for the prodrug, drug, and its inactive metabolite, 1-beta-D-arabinosyluracil. These observed pH-dependent in vitro rate constants were consistent with those for chemical hydrolysis determined from controls using Tris buffers. Hydrolysis of ancitabine to cytarabine is chemically, not enzymatically, mediated. The blood concentration-time course for administered compound was described by a two-compartment open model following a rapid intravenous injection of prodrug, drug, or metabolite in each of three rabbits. The in vivo conversion rate constant (kc) following a rapid intravenous prodrug injection was estimated by simultaneous nonlinear regression of ancitabine and cytarabine blood concentration-time courses using equations for two-compartment prodrug and drug with all possible models describing potential conversion sites. The best fit was obtained for the case allowing simultaneous conversion of the prodrug in both central and peripheral compartments to the drug in the central compartment with a common value for kc. The resulting kc value (0.09 h-1, three rabbits) is similar to that for chemical hydrolysis (0.07 h-1) at 38.8 degrees C. Reasons why this agreement is regarded as fortuitous are discussed.

Ancitabine↗
PubMed1984

Aqueous conversion kinetics and mechanisms of ancitabine, a prodrug of the antileukemic agent cytarabine.

The kinetics of conversion of the prodrug ancitabine to the anticancer drug cytarabine have been studied in aqueous solutions in the pH range of 1.5-10.7, temperature range of 19.5-80.0 degrees C, ionic strength range of 10(-4) to 1.5, and in the presence of several general-base catalysts. Under all conditions ancitabine was quantitatively converted to cytarabine. The pH-rate profiles were linear with slope = 1 in alkaline pH, becoming pH independent in the region of maximum stability at pH less than or equal to 4, where buffer catalysis was found to be insignificant and kobs approximately equal to (1.12 X 10(11) h-1)-exp [-10121 deg/T]. At 30 degrees C, pH less than or equal to 4, it is calculated that an aqueous ancitabine solution will maintain 90% of its initial concentration for 12 d. A novel method for measuring general-base catalysis in competition with predominating specific-base catalysis and in the presence of secondary salt effects at constant ionic strength was developed. Three mechanisms of hydrolytic prodrug conversion are proposed: nucleophilic hydroxide addition, general base-assisted nucleophilic water attack, and spontaneous water attack.

Ancitabine↗
PubMed1982

Drug stability in liposomal suspensions: hydrolysis of indomethacin, cyclocytidine, and p-nitrophenyl acetate.

First-order rate constants (kL) for hydrolysis of p-nitrophenyl acetate, cationic cyclocytidine, and anionic indomethacin in the presence of buffered liposomal suspensions of positive, negative, and neutral charge were compared to those determined in the corresponding buffers (kB) using the ratio, Rk = kL/kB. Association between the reactants and the liposomes was evaluated by comparing assays for concentration in the filtrates (CF) with the total concentration in the liposomal suspension (CT) using RC = CF/CT. Liposomes did not influence cyclocytidine hydrolysis rates and no association was observed (Rk congruent to RC congruent to 1). In contrast, indomethacin showed approximately 80% reduction in hydrolysis rate and approximately 80% liposome association value (Rk congruent to 0.2 congruent to RC). In neutral and negatively charged liposomal suspensions, p-nitrophenyl acetate displayed approximately 30% decrease in kB (Rk congruent to 0.7) together with approximately 90% liposomal association (RC congruent to 0.1). However, hydrolysis was greatly accelerated in positively charged liposomal suspensions. Loss was described by a biexponential equation where alpha is the fast and beta is the slow pre-exponential coefficient and alpha/beta/kB = 39:6:1. The observed relationships between hydrolysis rates and reactant-liposome associations are reconciled in terms of the hydrophilicity of the reactants and the potential influence of the liposomes on the expected transition states for the hydrolysis reactions.

Ancitabine↗
PubMed1981

Thermodynamic dependence of interfacial transfer kinetics of nonionized barbituric acid derivatives in two-phase transfer cell.

A theory was developed to describe interfacial transport kinetics of a series of drug homologs in a two-phase transfer cell. When tested, the theory held true for 5,5-disubstituted barbituric acid derivatives in a preequilibrated octan-1-ol = (pH 5) aqueous buffer system maintained at 37 degrees and stirred symmetrically at 50 and 100 rpm. Theoretical prediction of transfer kinetics was not possible in such a cell if the phases were stirred asymmetrically. For symmetric stirring, successful prediction of the transfer kinetics of any homolog in the series was possible from a knowledge of the partition coefficient and transfer kinetics of the parent compound, the partition coefficient of the homolog, and some easily determined system variables. The viscosity and density of the two phases and the phase-volume ratio were needed to define a system constant dependent on the solute diffusion coefficient, interfacial area, donor phase volume, and the boundary layer thickness for diffusion in the donor phase volume, and the boundary layer thickness for diffusion in the donor phase. A method is described to enable estimation of this constant from a knowledge of the transfer kinetics of the parent compound. The rank order of compounds in terms of their observed first-order transfer rate constants is shown to be dependent on the characteristics of the solvent system and stirring conditions employed, as well as on the physical chemistry of the solutes. The results are discussed in light of previously documented investigations.

Barbiturates↗
PubMed1981

Prodrug design.

Explore the source record for details and available documents.

Absorption↗
PubMed1980

Stability-indicating colorimetric assay for indicine N-oxide using TLC.

Aliquots of aqueous solutions in which indicine N-oxide may be degraded were mixed with 0.5 M formic acid (1:3) to adjust the pH to approximately 2-4 to quench the reaction and to ensure adequate TLC resolution. Silica-coated aluminum sheets were used to isolate indicine N-oxide by cutting the appropriate region from the chromatogram. By a modification of a known procedure, the silica gel then was treated with an acetic anhydride-diglyme mixture, and the mixture was heated to convert the drug to a pyrrole, which was then coupled with 4-dimethylaminobenzaldehyde to produce a color. The absorbance of the resulting solution was determined at 566 nm, and the apparent molar absorptivity, epsilon, based on the final indicine N-oxide concentration was 6.13 x 10(4). The recovery was approximately 92%, and the assays were readily reproducible with a coefficient of variation of 4.4%.

Chromatography, Thin Layer↗
PubMed1980

Calculation of partition coefficient of an unstable compound using kinetic methods.

A stirred transfer cell containing equal volumes of light liquid paraffin and an aqueous phase at 37 degrees was used to demonstrate the feasibility of calculating the partition coefficient of an unstable compound by kinetic analysis. Cyclohept-2-enone was chosen since it is a neutral molecule and, therefore, should have a pH-independent oil-water partition coefficient, KD. Moreover, this cyclic alpha, beta-unsaturated ketone undergoes hydrogen-ion-catalyzed hydration but is sufficiently stable at neutral pH to determine KD. The model system chosen represents first-order transfer between the aqueous (C1) and organic (C2) phases with simultaneous, reversible, first-order hydration. The transfer constants k'12 and k'21, were determined at 37 degrees in the absence of degradation where asymptotic values for C1 agreed with the observed equilibrium values in nonkinetic partitioning studies. The first-order rate constants for hydration in 0.1 N HCl were determined at 37 degrees in the absence of the organic phase. Partitioning with simultaneous hydration when was studied using 0.1 N HCl and light liquid paraffin. Data were analyzed by nonlinear regression based on the equation for C1 as a function of time. The values for k'12 and k'21 from these experiments were comparable to the estimates obtained under stable conditions. This agreement demonstrates that simultaneous degradation and partitioning can be analyzed for k'12 and k'21, thus permitting calculation of the partition coefficient (i.e., KD = k'12/k'21) that would be observed if the drug were stable.

Biodegradation, Environmental↗
PubMed1980

Simultaneous partitioning and hydrolysis kinetics of amoxicillin and ampicillin.

The kinetics of ampicillin and amoxicillin partitioning with simultaneous acid-catalyzed hydrolysis were studied in a stirred transfer cell containing isobutanol as the extract and aqueous hydrochloric acid (0.1-0.5 N) as the raffinate at 37 degrees. Biexponential data for the concentration in both the raffinate (C1) and the extract (C2) as a function of time were analyzed simultaneously by nonlinear regression to estimate the apparent first-order rate constant for transfer from hydrochloric acid to isobutanol (k '12), the reverse transfer constant (k '21), and the hydrolysis rate constant (k). Agreement between k values determined in the presence of simultaneous partitioning and those determined in the absence of partitioning (k app) verified the nonlinear estimates. Apparent partition coefficients, which represent the values that would be obtained in the absence of hydrolysis K'D = C1 infinity/C2 infinity), were estimated from K'D = k'12/k'21. During terminal monoexponential loss, where C1 approximately equal to Y'e-beta t and C2 approximately equal to Z'e-beta t, the kinetically controlled C2/C1 ratio (r) is described by [K'12/K'21-beta)], which decreases with decreasing kappa values until r approaches K'D. The difference between the terminal concentration ratio, r, and its corresponding partition coefficient, K'D, is a measure of the degree to which kinetic processes control distribution. Both ampicillin and amoxicillin showed kinetic control of the distribution ratios in 0.5 N HCl, where the hydrolysis rate constant was significant relative to the distribution rate constants. Ampicillin had r approximately equal to 1.74 and K'D approximately equal to 0.92; amoxicillin had r approximately equal to 0.95 and K'D approximately equal to 0.65. As the (K'12 + K'21/k ratio increased, the r values approached K'D so that in 0.1 N HCl, r approximately K'D = 0.33 for amoxicillin and r approximately 0.6 and K'D approximately 0.56 for ampicillin. In general, amoxicillin distribution rate constants (K'12 + K'21) were roughly twice those of ampicillin, whereas ampicillin K'D and r values were nearly double those of amoxicillin. Thus, the kinetic and thermodynamic rank orders are opposite. This result may have implications in drug design via molecular modification.

Amoxicillin↗
PubMed1976

Critical analysis of "flip-flop" phenomenon in two-compartment pharmacokinetic model.

Computer simulations were used to examine the effect of first-order absorption on the disposition of one- and two-compartment model drugs. Two-compartment systems that attain a clinically acceptable beta-phase after rapid intravenous injection were perturbed by introduction of drug via first-order absorption. The validity of perceiving such a system as a potential "flip-flop" model was tested by comparing the negative slopes of log-linear plasma-time profiles to known values for ka and beta for various values of ka, k12, k21, and k10. Although most log-linear plots showed excellent correlation coefficients (r2 greater than 0.996), their negative slopes (S) did not represent either ka or beta under various combinations. A similar consideration of the one-compartment model enabled a comparison to be made between the two systems. Maximum negative errors were observed for both one- and two-compartment drugs as ka leads to k2 or beta, respectively. The value for S provided a good estimate of the absorption rate constant, ka, when k2 greater than or equal 2ka (one compartment) or beta greater than or equal 2ka. The elimination rate constant (k2 or beta) could be obtained from S for all one-compartment and some two-compartment drugs when the value of ka was approximately twice that of k2 or beta. Large positive errors also were observed with certain two-compartment drugs where the ratio of the four rate constants apparently linearized a nonlinear plasma profile. Conditions wherein S may be expected to approach beta wherein S approaches ka are clearly defined.

Absorption↗
PubMed1976

Testing of drug delivery systems for use in the treatment of narcotic addiction.

The evaluation of the drug release characteristic of four naltrexone delivery systems has been carried out together with the development of analytical techniques and an investigation of the metabolic profile of naltrexone. Pharmacologic evaluation of the four delivery systems in the mouse indicated significant analgesic antagonism for a period of from 16-22 days. Further evaluation of one of these systems by measurement of the rate of excretion of radioactivity after administration of radiolabelled naltrexone in the delivery system confirmed that significant release occurs for a time period of about 15 days. Electron capture gas-liquid chromatographic assays for naltrexone and naloxone in plasma or urine have been developed that yield linear calibration curves and are sensitive to one ng/ml. Studies on naltrexone disposition indicate that (a) binding to plasma proteins in several species varies from 20-26%, (b) distribution of drug from blood is extremely rapid and extensive, (c) beta-naltrexol is a major metabolite of naltrexone in man, monkey and guinea pig among six species studies, whereas alpha-naltrexol is a minor metabolite in the monkey and guinea pig only, and (d) metabolic reduction of naltrexone occurs in the 100,000 x g supernatant of guinea pig liver. Pharmacokinetic studies of naltrexone in the dog and monkey indicate that the drug is rapidly distributed and eliminated, has a very large apparent volume of distribution and a total body clearance greater than the rate of liver blood flow.

Animals↗
PubMed1975

Kinetics and mechanisms of degradation of the antileukemic agent 5-azacytidine in aqueous solutions.

The hydrolytic degradation of 5-azacytidine was studied spectrophotometrically as a function of pH, temperature, and buffer concentration. Loss of drug followed apparent first-order kinetics in the pH region below 3. At pH less than 1,5-azacytosine and 5-azauracil were detected; at higher pH values, drug was lost to products which were essentially nonchromophoric if examined in acidic solutions. The apparent first-order rate constants associated with formation of 5-azacytosine and 5-azauracil from 5-azacytidine are reported. Above pH 2.6, first-order plots for drug degradation are biphasic. Apparent first-order rate constants and coefficients for the biexponential equation are given as a function of pH and buffer concentration. A reaction mechanism consistent with the data is discussed together with problems associated with defining the stability of the drug in aqueous solutions. At 50 degrees, the drug exhibited maximum stability at pH 6.5 in dilute phosphate buffer. Similar solutions were stored at 30 degrees to estimate their useful shelflife. Within 80 min, 6 times 10(-4) M solutions of 5-azacytidine decreased to 90% of original potency based on assumptions related to the proposed mechanisms.

Azacitidine↗
PubMed1975

Testing of drug delivery systems for use in the treatment of narcotic addiction.

The evaluation of the drug release characteristic of four naltrexone delivery systems has been carried out together with the development of analytical techniques and an investigation of the metabolic profile of naltrexone. Pharmacologic evaluation of the four delivery systems in the mouse indicated significant analgesic antagonism for a period of from 16-22 days. Further evaluation of one of these systems by measurement of the rate of excretion of radioactivity after administration of radiolabelled naltrexone in the delivery system confirmed that significant release occurs for a time period of about 15 days. Electron capture gas-liquid chromatographic assays for naltrexone and naloxone in plasma or urine have been developed that yield linear calibration curves and are sensitive to one ng/ml. Studies on naltrexone disposition indicate that (a) binding to plasma proteins in several species varies from 20-26 per cent, (b) distribution of drug from blood is extremely rapid and extensive, (c) beta-naltrexol is a major metabolite of naltrexone in man, monkey and guinea pig among six species studied, whereas alpha-naltrexol is a minor metabolite in the monkey and guinea pig only, and (d) metabolic reduction of naltrexone occurs in the 100,000 x g supernatant of guinea pig liver. Pharmacokinetic studies of naltrexone in the dog and monkey indicate that the drug is rapidly distributed and eliminated, has a very large apparent volume of distribution and a total body clearance greater than the rate of liver blood flow.

Animals↗