Biopharmaceutics and clinical pharmacokinetics , Biopharmaceutics and clinical pharmacokinetics , کتابخانه دیجیتال جندی شاپور اهواز

Previous publications described computer-aided methodology for assessing the feasibility of designing prolonged release oral dosage forms containing linear-disposition drugs. Those methods determined all useful release rates and examined those rates to decide whether product development was warranted. The present study developed software to obtain similar information for phenytoin, which exhibits Michaelis–Menten disposition. The values for Vmax, Km, and Vd in 27 patients were employed to assess the ability of prolonged absorption to maintain steady-state plasma concentrations between 10 and 20 mg/liter following oral administration at 8-, 12-, and 24-hr intervals. Phenytoin steady-state plasma concentrations in this range were controlled by elimination and were not extended by prolonged absorption. Furthermore, single i.v. bolus doses resulting in an initial plasma level of 20 mg/liter provided concentrations above 10 mg/liter for ~1 to 3 days. When an oral multiple-dose regimen was found to maintain steady-state concentrations between 10 and 20 mg/liter, that dose and interval produced concentrations within that range regardless of the absorption rate. While absorption rate was not important, each patient’s dose ranges were extremely narrow, emphasizing that dose size was the dominant factor in the control of phenytoin levels.

The utilization time for a parenteral prodrug solution with a bioavailable fraction of unity was defined as the time during which the total of the prodrug concentration and the drug concentration equals or exceeds 90% of the initial prodrug concentration. This utilization time was calculated as a function of pH, buffer, and temperature using the experimentally determined rate expressions for bacampicillin and talampicillin. The results were compared to the shelf life of ampicillin solutions under identical storage conditions. First-order rate constants were determined for conversion of the prodrugs to ampicillin (kc), for β-lactam degradation of the prodrugs (knc), for the overall loss of prodrugs (ksum), and for β-lactam degradation of ampicillin (kh) in aqueous solutions at 25.0 to 60.0°C, µ = 0.5, in the pH range 0.90 to 8.4. Loss of bacampicillin proceeded primarily by degradation at pH levels below 4 but was due predominantly to conversion at pH levels above 5. Loss of talampicillin was due primarily to conversion throughout the entire pH range. While the prodrug utilization times were approximately twice the shelf life of ampicillin in acidic solutions, ampicillin was significantly better in neutral solutions. The results illustrate the potential for increased prodrug storage periods when utilization time is defined on the basis of the bioactivity rather than on the prodrug concentration alone.

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 < 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. These actual UTratio versus pH profiles were interpreted in terms of the theory established using the simulations.

Classical methods employing pharmacokinetic data to calculate zero-order release rates for sustained release products require that a constant-rate drug delivery system must have a duration which is exactly equal to the desired dosage interval. This traditional approach fails to establish the minimum acceptable duration and also fails to provide any flexibility in the formulation goal. While it does calculate one pair of duration and dose values, there are infinite pairs of values capable of maintaining the desired plasma concentrations using the selected dosing interval. In the current method, computer simulations are used to establish the boundary conditions within which any pair of duration and dose values will maintain the desired levels when administered on the chosen dosing interval. By comparing the boundary conditions for every subject in a group, a single set of conditions which would work for the entire group can be selected. These final limits represent the broadest specifications for zero-order drug delivery system design for that particular drug combined with the plasma concentration goals and the desired dosing interval. The method is illustrated using theophylline pharmacokinetics.

The stability of captopril in aqueous solution at 32°C was studied in the pH range 6.6 to 8.0 under controlled oxygen partial pressure (90–760 mm Hg) with and without the addition of cupric ion. The oxidation product, captopril disulfide, was found to be the sole degradation product. A change in reaction rate from first order to zero order occurs as the captopril concentration decreases. The concentration at which this transition takes place is a function of the pH, oxygen partial pressure, and cupric ion concentration. The apparent first-order rate constants show a first-order dependency on both the oxygen partial pressure and the cupric ion concentration. However, the apparent zero-order rate constants show a first-order dependency on oxygen partial pressure and a second-order dependency on cupric ion concentration. As the pH increases from 6.6 to 8.0, the first-order process becomes more predominant. A mechanism which consists of cupric ion- and molecular oxygen-catalyzed oxidation is proposed to explain those observations.

The method provides an a priori assessment of the maximum allowable flexibility in the rate of release from a prolonged-release formulation. The clinical pharmacokinetic parameters describing the drug candidate are employed to calculate the ranges of rate constants and doses required for the formulation to provide a selected therapeutic duration. For a given patient, there may be an infinite number of combinations of release rate constants and dose sizes which will maintain steady-state plasma drug concentrations within a desired range when the formulation is administered at the selected dosing interval. Computer simulations of steady-state plasma concentrations are employed to establish the ranges for all of the acceptable rate constants and doses for each member of a group. The entire group is then examined to define the range of release rate constants and doses which would provide a useful formulation for every member in the group. Literature values for theophylline clinical pharmacokinetics in children and adults have been employed to illustrate the application of this method. The method is unique in that it provides an entire range of release rates on which to gauge the feasibility for success.

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.

First-order rate constants (kL) for hydrolysis of p-nitro-phenyl 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≃RC≃1). In contrast, indomethacin showed ~80% reduction in hydrolysis rate and ~80% liposome association value (Rk≃0.2≃RC). In neutral and negatively charged liposomal suspensions, p-nitrophenyl acetate displayed ~30% decrease in kB (Rk≃0.7) together with ~90% liposomal association (RC≃0.1). However, hydrolysis was greatly accelerated in positively charged liposomal suspensions. Loss was described by a biexponential equation where α is the fast and β is the slow pre-exponential coefficient and α/β/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.

Recent interest in prodrugs as well as other drug delivery systems has included the control of drug release for the purpose of extending the duration of therapeutic blood levels. While zero-order release rates are generally considered ideal, many systems approach apparent first-order kinetics. These cases may successfully prolong duration if the rate constant for drug delivery (ka) is rate-limiting relative to the elimination rate constant (k or β). For a given drug there is only one optimum rate-limiting input constant which will provide the maximum duration of therapeutic activity for a given dose. This was demonstrated using computer simulations to examine the effect of variations in dose and R (R = ka/k or ka/β) upon the duration, T, of 1- and 2-compartment model drugs administered by rate-determining first-order input. When dose is held constant, an optimum R, Ropt, exists at which duration is maximal (T = Tmax). When ka is fixed, an optimum value for dose, [D0]opt, provides the greatest duration per unit mass. Equations were derived which enable estimation of Ropt, T, Tmax, and [D0]opt when input is rate-determining. The accuracy of these estimates was determined as a function of R. The equations provide estimates with less than 5% error when R ⩽ 0.09. The administration of a 1- or 2-compartment model drug at estimates within the limit, 0.09 < R ⩽ 0.34, provides a duration T ⩾ 0.95 Tmax. A practical approach for maximizing duration by manipulation of dose and ka is described for drugs with known biological half-life, Vd and minimum effective concentration. The results are significant in that they provide a means for both assessing the feasibility of increasing the duration of drug action by prodrug formation and for evaluating the experimental results by comparison with the theoretical optimum.

Chemischer InformationsdienstVolume 4, Issue 26 Preparative Organic Chemistry ChemInform Abstract: KATALYSE DES ALPHA-WASSERSTOFF-AUSTAUSCHS 13. MITT. BIFUNKTIONELLE KATALYSE DER DEDEUTERIERUNG VON (2-D)ISOBUTYRALDEHYD DURCH POLYAETHYLENIMINE JACK HINE, JACK HINESearch for more papers by this authorEDWARD F. GLOD, EDWARD F. GLODSearch for more papers by this authorROBERT E. NOTARI, ROBERT E. NOTARISearch for more papers by this authorF. E. ROGERS, F. E. ROGERSSearch for more papers by this authorFRANK C. SCHMALSTIEG, FRANK C. SCHMALSTIEGSearch for more papers by this author JACK HINE, JACK HINESearch for more papers by this authorEDWARD F. GLOD, EDWARD F. GLODSearch for more papers by this authorROBERT E. NOTARI, ROBERT E. NOTARISearch for more papers by this authorF. E. ROGERS, F. E. ROGERSSearch for more papers by this authorFRANK C. SCHMALSTIEG, FRANK C. SCHMALSTIEGSearch for more papers by this author First published: June 26, 1973 https://doi.org/10.1002/chin.197326205AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume4, Issue26June 26, 1973 RelatedInformation

This is a review (and in some cases an analysis) of selected pharmacokinetic studies on drugs with closely related chemical structures. It is not an attempt to survey all of the work that has been reported in the field of biopharmaceutics and pharmacokinetics, nor is it a summary of all studies involving alteration of drug absorption, distribution, and excretion through molecular modification. Several recent publications collectively serve that purpose, and these are cited within the text. This review is an attempt to stress the significance of pharmacokinetics in drug design and to illustrate the main points using examples selected from the literature.