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 (k _nc), its conversion (k _c) to drug, and the subsequent drug degradation (k _h) 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 (UT_ratio) was calculated using a wide range of values for the three rate constants. Three-dimensional plots relating the UT_ratio to the k _c, k _nc, and k _h 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 (k _nc < k _h) 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 k_nc, k _c, and k _h. Two ampicillin prodrugs were used as models to calculate actual UT_ratio versus pH profiles. Intravenous solutions showed modest gains in the UT_ratio in the acid region, whereas oral solutions reached a UT_ratio as high as 22 by combining favorable rate constants with increased bioavailability. These actual UT_ratio versus pH profiles were interpreted in terms of the theory established using the simulations.     

Pharmacokinetics of ampicillin and its prodrugs bacampicillin and pivampicillin in man

Five healthy fasting male subjects were each given single doses of intravenous ampicillin (471 mg), oral ampicillin tablets (495 mg), oral bacampicillin hydrochloride tablets (562 mg ampicillin equivalent), and oral pivampicillin hydrochloride capsules (491 mg ampicillin equivalent) in a crossover experiment. The resulting concentrations of ampicillin were determined in plasma and urine. The pharmacokinetic analysis was made according to a two-compartment open model. The total distribution volume of unbound ampicillin during the disposition phase was 0.247 ± 0.045 (sd) liter/kg, which is only slightly more than the extracellular fluid, suggesting that tissue binding and intracellular distribution of ampicillin are limited. The bioavailability of the esters bacampicillin (86 ± 11%) and pivampicillin (92± 18%) was significantly greater than that of ampicillin (62 ± 17%); however, the difference between the esters was not statistically significant. The absorption for all drugs given orally proceeded at a constant rate, suggesting zero-order release rates from the products. The absorption rate was highest for bacampicillin (0.89 ± 0.39% of dose absorbed per minute), followed by pivampicillin (0.64 ± 0.19) and ampicillin (0.58 ± 0.16). Bacampicillin also had the shortest lag time for the start of absorption (7.0 ± 0.9 min) under the present conditions. Thus, in comparison with ampicillin, the esters have a higher bioavailability, which, in fact, is close to the theoretically highest possible value by clearance concepts. The higher bioavailability in connection with higher absorption rates may be clinically important in ampicillin treatment by the oral route.This work was supported by the Swedish Medical Research Council, Project No. 522 (L. O. B.).     

Oral cyclacillin interacts with the absorption of oral ampicillin,amoxycillin, and bacampicillin

Summary The relative bioavailabilities of single oral doses of ampicillin, amoxycillin, and bacampicillin were compared with and without concomitant administration of a six-times higher molar dose of cyclacillin. As the absorption of cyclacillin has been shown to involve a capacity-limited transport system in animals, it was selected as the reference compound for the study. The treatments were given to 14 fasting volunteers using a randomized, complete crossover design. The drugs in plasma and urine were determined by liquid chromatography. Renal clearance was 17%, 10% and 19% lower when ampicillin, amoxycillin, and bacampicillin were given together with cyclacillin. Consequently, differences in the relative bioavailability were based on urinary recoveries assuming constant non-renal clearance. When amoxycillin was given with cyclacillin there was a 67% delay in the time of the plasma peak concentration, and an 8% lower urinary recovery than when it was given alone. There was a 50% and 33% delay in the t_max of ampicillin and bacampicillin when combined with cyclacillin; the urinary recovery of ampicillin in the combination was 10% lower but that of bacampicillin was similar. There was also a 20% delay in the t_max of cyclacillin when combined with amoxycillin. The differences in renal clearance indicate an interaction in the renal elimination of the drugs, but the effect was probably not the explanation for the marked shift in time of the absorption of these rapidly absorbed drugs. The results support the existence of a capacity-limited transport system for aminopenicillins in the human gut.     

Potential Improvement in the Shelf Life of Parenterals Using the Prodrug Approach: Bacampicillin and Talampicillin Hydrolysis Kinetics and Utilization Time

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 (k _c), for -lactam degradation of the prodrugs (k _nc), for the overall loss of prodrugs (k _sum), and for -lactam degradation of ampicillin (k _h) 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.     

Determination of water in penicillins using fast Karl Fischer reagents and electronic end-point optimization

When using conventional Karl Fischer reagents for titration of water in penicillins, decomposition products (i.e. penicilloic acid) are shown to be partly cotitrated. Water in ampicillin, bacampicillin, carboxybenzylpenicillin and cloxacillin was titrated with slow and fast reagents and the differences in the results obtained were compared with the content of penicilloic acid determined mercurimetrically. A simple electronic control unit has been developed to optimize the speed of titration.     

Characterization of primary recall in vitro lymphocyte responses to bacampicillin in allergic subjects

BACKGROUND: Antigen-specific cell lines or clones are often used as models of drug-specific allergy. However, cloning procedures are time consuming, and the repeated antigen stimulation cycles as well as the addition of various growth enhancers may affect the in vivo relevance of these systems. OBJECTIVE: Using bacampicillin-allergic subjects, we wanted to investigate the applicability of primary recall in vitro lymphocyte responses to characterize type I and type IV allergy. The sensitivity and specificity of LTT (Lymphocyte transformation test), when used as an in vitro diagnostic tool, were also assessed. METHODS: A total of 39 patients with symptoms of type I (rhinitis) or type IV (allergic contact dermatitis, ACD) allergy following occupational exposure to bacampicillin, were included. Ten individuals without penicillin allergy or occupational exposure to bacampicillin served as controls. All subjects were LTT tested. Four patients with rhinitis and two patients with ACD were available for studying the immunophenotype and the TCR-Vbeta repertoire of bacampicillin induced lymphoblasts as well as the cytokine profiles and expression of the activation markers CD23 and CD134 in primary PBMC cultures. RESULTS: LTT was positive in 87% and at least one of the skin tests was positive in 85% of the patients with allergic symptoms. 69% of the patients with type I allergies were patch test-positive. Results from LTT and skin test correlated in 87% of the cases. The combined sensitivity of LTT and skin tests was 92%. The specificity of LTT was 90% in healthy controls. Bacampicillin induced lymphoblasts were mainly CD4 + in both ACD and rhinitis patients. The TCR-Vbeta profiles of the predominant CD4 + lymphoblasts were heterogeneous with individual skewing towards Vbeta2, Vbeta3, Vbeta5.1 and/or Vbeta14. An increased expression of IFNgamma was detected in bacampicillin treated PBMC cultures from the ACD but not from rhinitis patients. IL-5 was detected in bacampicillin exposed PBMC cultures from all patients but not from healthy controls. This Th2 environment could also be verified by CD23 and CD134 expression. CONCLUSION: LTT and skin tests are equally sensitive in identifying bacampicillin allergic subjects. When the two tests are combined, the sensitivity increases. The patch test is useful not only for detection of type IV but also for the identification of type I allergies. When using primary PBMC cultures, IFNgamma is the most suitable cytokine to discriminate between type I and type IV allergy. IL-5 can possibly be used as a general marker for bacampicillin induced allergy. Thus, primary cell cultures may be considered as an alternative to T-cell lines or clones for the study of drug induced allergy.     

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 vitrodissolution 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 vivoresponse 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 vivoand mean dissolution time in vitrowas also found which thus demonstrates the usefulness of moment analysis for obtaining an in vivo-in vitrorelationship. This relationship was compared to a correlation found between the mean dissolution time in vitroand the empirical maximum plasma concentration of bacampicillin.