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 adsorption for all drugs given orally proceeded at a constant rate, suggesting zero-order release rates from the products. The adsorption 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.     

Bacampicillin Hydrochloride: Chemistry,Pharmacology, and Clinical Use

Bacampicillin hydrochloride is an orally administered ester of ampicillin that is rapidly and completely hydrolyzed in vivo to ampicillin. The most notable advantage of bacampicillin over ampicillin is its superior bioavailability — bacampicillin achieves significantly higher blood and tissue levels and attains peak blood levels more rapidly than equimolar doses of oral ampicillin. In addition, the percentage of an oral dose of ampicillin that is absorbed decreases sharply as the size of the dose is increased from 500 mg to 2 g; this phenomenon is not observed with equipotent doses of bacampicillin. The enhanced absorption of bacampicillin in the upper gastrointestinal tract results in a frequency of diarrhea that appears to be markedly lower than that of ampicillin and similar to that observed with amoxicillin. Apart from the sizable differences between bacampicillin and ampicillin with regard to oral absorption, the pharmacokinetic and pharmacologic profiles of these two agents are essentially identical. Twice daily dosing (pulse dosing) with bacampicillin has been shown in numerous clinical trials to be of equivalent efficacy to ampicillin given four times daily or amoxicillin given three times daily in the treatment of infections of the upper respiratory tract, lower respiratory tract, skin and soft tissues, and urinary tract. The unanswered question is whether twice daily ampicillin or amoxicillin would yield similar results.     

The effect of sudanese food and chloroquine on the bioavailability of ampicillin from bacampicillin tablets

The effect of Sudanese food and chloroquine on the bioavailability of ampicillin from bacampicillin was investigated. The bioavailability of ampicillin was determined using the urinary excretion method. The urinary levels of ampicillin were measured chemically. Bacampicillin capsules were administered: (i) under different dietary conditions; and (ii) on an empty stomach together with chloroquine phosphate tablets. Unlike the case of ampicillin capsules, neither food nor chloroquine affected the bioavailability of ampicillin from bacampicillin capsules. The difference between ampicillin and bacampicillin capsules with respect to the effect of food and chloroquine on ampicillin bioavailability is discussed.     

Enhanced Bioavailability of Cefoxitin Using Palmitoylcarnitine. II. Use of Directly Compressed Tablet Formulations in the Rat and Dog

The performance of tablets containing the absorption enhancer palmitoylcarnitine chloride (PCC) and the antibiotic cefoxitin (CEF) was determined by direct placement of tablets in the rat stomach, small intestine, and colon. While the bioavailability (F) of tablets containing 12 mg CEF without PCC ranged from 0.6 to 3.9%, the addition of 24 mg PCC resulted in an enhanced CEF bioavailability in the rat colon (mean ± SD: F = 57 ± 19%) and rat jejunum (F = 71 ± 16%) but not in the rat stomach. Following oral administration to dogs, tablets of 200 mg CEF without or with 600 mg PCC resulted in the same low bioavailabilities (7.0 ± 10.3 and 7.0 ± 3.6%, respectively). However, when these tablets were enteric coated, PCC improved CEF bioavailability from 2.44 ± 1.84 to 29.0 ± 13.4%. Therefore, the use of enteric-coated direct compressed tablets containing PCC and direct compression excipients improved the peroral bioavailability of a poorly absorbed compound.     

The Oral Absorption of Ampicillin,Pivampicillin and Amoxycillin in Infants and Children

Abstract: The oral absorption of comparable doses of mixtures of ampicillin, amoxycillin and pivampicillin was studied in 38 children from 6 months to 6 years of age. Plasma concentrations following pivampicillin and amoxycillin were higher than those following the administration of ampicillin. No significant difference was found between amoxycillin and pivampicillin. The oral absorption of pivampicillin mixture was further studied in 12 infants, 0–1 month and 1–5 months of age. The absorption was faster in infants and children more than 6 months of age than in the 1–5 months group. The excretion, indicated by the slope of the plasma concentration curve, was delayed in infants less than one month of age. The oral absorption of amoxycillin and pivampicillin from tablets was also studied in 12 infants and children, 6 months-6 years of age, in the same doses as when mixtures were studied and was more complete with pivampicillin than with amoxycillin. The absorption of pivampicillin was more complete from tablets than from mixture. Also with amoxycillin there was a trend towards more efficient absorption from tablet than from mixture.     

Evaluation of the absorption from 15 commercial theophylline products indicating deficiencies in currently applied bioavailability criteria

The biovailability of theophylline from alcoholic and aqueous oral solutions was compared to that from an intravenous dose in 12 normal adults. The alcoholic elixir surprisingly gave rise to a significantly greater (114 ±14%, mean±sd amount absorbed than did the intravenous dose. The aqueous solution (99±8%) and intravenous dose were statistically indistinguishable in this respect, and, furthermore, the extent of absorption from a 300-mg dose of the aqueous solution was 99±10% of that from a 500-mg dose, and not statistically different. The aqueous solution was thus employed in three subsequent studies as a standard with which to compare 13 different types of theophylline tablets, all marketed in the United States. Of the 13 tablets, eight showed bioavailability statistically distinguishable from that of the standard. Nevertheless, for only two tablets could it be claimed with 95% confidence that the bioavailability was less than 95%. For none can it be stated at this confidence level that the bioavailability is less than 90%. Bioavailability studies should include criteria of clinical significance in addition to criteria of statistical significance. Contrary to the usual rationale behind choice of a bioavailability standard, nine of the 12 uncoated tablets appeared to allow more rapid absorption of theophylline than did the standard oral solution, an aqueous syrup. Increasing the dose of syrup decreased the rate of theophylline absorption. Orally administered drug solutions may have properties more absorption rate limiting than the disintegration of many brands of tablet.This work was supported by FDA Contract No. 223-74-3145. Data management and analysis were achieved largely by the NIH-sponsored PROPHET system (ref.Proc. Natl. Comput. Conf. Exposition 43: 457, 1974). Dr. Guentert was supported by the Swiss National Science Foundation.     

Ampicillin in portal and peripheral blood and bile after oral administration of ampicillin and pivampicillin

Summary The concentration of ampicillin in serum and bile has been determined in 10 patients after oral administration of equivalent doses of ampicillin (500 mg) and pivampicillin (700 mg). Ampicillin produced maximum concentrations in bile twice as high as in serum, and, after pivampicillin, peak levels of ampicillin occurred earlier and were approximately four times greater than after ampicillin. In 11 other patients, ampicillin was determined simultaneously in peripheral and portal blood, collected from an umbilical vein catheter, following a dose of pivampicillin or an intravenous injection of ampicillin. The peak concentration of ampicillin after an oral dose was twice as high in portal blood as in peripheral blood. There appears to be passive transfer of ampicillin from blood to bile.     

Studies on the pharmacokinetic equivalence of pivampicillin base and hydrochloride in capsules and tablets (author's transl)

Absorption and urinary excretion of pivampicillin as hydrochloride and as base were studied following administration of four different formulations to 12 healthy volunteers in a cross-over study. A fluorimetric assay of ampicillin was adapted to be used with an Auto Analyzer system. The plasma concentrations observed are comparable to those reported in the literature. The amount of drug absorbed is the same for all four medications whereas absorption is more rapid from tablets than from capsules. Base and hydrochloride of pivampicillin are equivalent with respect to pharmacokinetic behaviour. So, the formulation itself seems to be more important for biological equivalence than the ionisation of the drug used in the formulation.     

Bacampicillin uptake is shared with thiamine in Caco-2 cells

Bacampicillin was developed as a prodrug to improve the intestinal absorption of its metabolite ampicillin. This study was undertaken to characterize bacampicillin transport in Caco-2 cells. The uptake of bacampicillin in Caco-2 cells was significantly greater than those of ampicillin and pivampicillin. An Eadie-Hofstee plot obtained from 5-min uptake of 0.2-5 mM bacampicillin was linear, indicating the presence of a saturable transport system for bacampicillin with K(m) and V(max) of 3.6 mM and 23.9 nmol/mg protein/min, respectively. Hydrophilic organic cations such as choline, cimetidine, guanidine, nicotinamide, 1-methylnicotiamide, and tetraethylammonium failed to modulate bacampicillin uptake in Caco-2 cells whereas diphenhydramine, procainamide, and thiamine significantly depressed it. Moreover, when thiamine was preloaded in Caco-2 cells, bacampicillin uptake was significantly increased, indicating that this cationic vitamin was capable of trans-stimulating bacampicillin transport across the apical membrane of Caco-2 cells. However, trans-stimulated bacampicillin uptake was not observed in the presence of diphenhydramine. Bacampicillin uptake increased with elevation of the medium pH, and the known modulators of thiamine transport such as amiloride and oxythiamine significantly inhibited bacampicillin uptake. Thiamine also significantly decreased the apical-to-basolateral transport of bacampicillin across Caco-2 cell monolayers. However, thiamine did not exert any modulating effect on pivampicillin uptake and its apical-to-basolateral permeation in Caco-2 cells. These results suggest that bacampicillin is transported in Caco-2 cells, sharing a carrier-mediated system with thiamine.     

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.     

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.     

The pharmacokinetics of intravenous and oral sulpiride in healthy human subjects

Summary The pharmacokinetics of sulpiride was studied in 6 healthy volunteers after intravenous and oral (tablets) administration of 100 mg. An open two- and in two subjects a three-compartment model was applied following intravenous administration. The average total distribution volume during the terminal slope was 2.72±0.66 l/kg and total systemic clearance was 415±84 ml/min. The serum half-life of the terminal slope following intravenous administration averaged 5.3 h (range 3.7–7.1 h) according to the two-compartment model. In two subjects the half-lives were 11.0 and 13.9 h when the three-compartment model was applied. Determination of urinary excretion rates of unchanged sulpiride indicated a half-life of 7.15 h. Following intravenous administration, 70±9% of the dose was recovered unchanged in urine within 36 h; the mean renal clearance was 310±91 ml/min. Sulpiride was absorbed slowly, with peak concentrations appearing between 3 and 6 h after oral administration. The recovery of unchanged drug in urine following oral administration was 15±5% of the dose, with a mean renal clearance of 223±47 ml/min. The bioavailability determined from combined plasma and urine data was only 27±9%. The low bioavailability was probably due to incomplete absorption.     

An evaluation of maprotiline intravenous kinetics and comparison of two oral doses

Summary The kinetics of maprotiline have been evaluated in six normal volunteers following rapid intravenous administration of 75 mg. Blood levels could be resolved using a biexponential equation. Mean estimates of half-life, volume of distribution and systemic clearance were 40±15 h, 51.7± 18.01 l/kg and 0.92±0.24 l/kg/h, respectively. Blood/plasma concentrations varied between subjects from 0.77 to 1.64. A comparison of the bioavailability of two oral doses (a 75 mg tablet and three 25 mg tablets) was carried out in the same volunteers. No significant difference was observed between the maprotiline concentrations obtained for the two doses at sampling times up to 26 h. No significant difference was found in the area under the concentration vs. time curves for the two doses. Equivalent bioavailability can be assumed. On the basis of the intravenous injection study, systemic bioavailability averaged 66% and 70% for the 75 mg and three 25 mg tablets respectively.     

Pharmacokinetics and bioavailability of diacetolol,the main metabolite of acebutolol

Summary The pharmacokinetics and bioavailability of diacetolol, the principal metabolite of acebutolol, were studied in 6 healthy subjects. Plasma concentrations were determined following a single intravenous injection of diacetolol 100 mg and three oral doses of diacetolol 100, 400 and 800 mg, in random order. The average oral bioavailability of diacetolol was F: 0.302±0.052 (100 mg), 0.363±0.052 (400 mg) and 0.426±0.068 (800 mg); the differences are not significant. The mean plasma half-life of the terminal phase, 7.94±0.26 h after intravenous administration, was significantly higher than after oral administration 12.27±1.00 h (100 mg), 12.82±1.59 h (400 mg) and 13.05±1.22 h (800 mg) (p<0.02 to 0.05); the mean urine half-lives of the terminal phase were not significantly different. Renal clearance of diacetolol 10.2±0.81·h^–1 represented about two-thirds of total body clearance 15.9±1.21·h^–1. The results suggest either a first-pass effect or incomplete absorption of diacetolol after oral administration.     

Rectal absorption enhancement of rate-controlled delivered ampicillin sodium by sodium decanoate in conscious rats

Because of the relatively poor intestinal absorption of ampicillin sodium, efforts have been made to enhance ampicillin absorption by co-administration of absorption promoters. In the present study the enhancing effect of sodium decanoate on rate and extent of rectal ampicillin absorption in rats has been evaluated after rate-controlled and site-controlled delivery of aqueous solutions. Rectal absorption without enhancer was extremely low (8±7%), and the addition of 0.032M sodium decanoate gave comparable values. However, administration in 0.16M decanoate considerably increased ampicillin bioavailability, to 79±30%, whereas the absorption rate was not significantly affected.     

Randomised trial of pivampicillin plus pivmecillinam vs. pivampicillin in children and young adults with chronic obstructive pulmonary disease and infection with Haemophilus influenzae

A prospective, randomised, single-blind comparative trial was carried out to determine whether double beta-lactam treatment with pivampicillin plus pivmecillinam is more effective than pivampicillin alone in the treatment of recurrent and chronic lung infections with Haemophilus influenzae in patients with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF). Fifty-six children and young adults with COPD or CF were randomised to the clinical study. The patients were allocated at random to receive perorally either pivmecillinam, 40 mg/kg/day, combined with pivampicillin, 50 mg/kg/day, or pivampicillin 50 mg/kg/day alone for 14 days. A cross-over pharmacokinetic study using the same drugs was carried out in 10 CF patients to determine the antibiotic concentrations in serum and sputum after a single dose of each drug. The clinical study showed no significant differences in clinical scoring, lung function tests or adverse events after treatment with pivampicillin plus pivmecillinam or pivampicillin alone. Follow-up microbiological evaluation 2 and 6 weeks after the end of treatment showed that the offending pathogen was eradicated in 68% of the patients treated with pivampicillin plus pivmecillinam and in 67% of the patients treated with pivampicillin alone. Reinfection with another biotype was more common in the combination group (50% vs. 21%) than in the pivampicillin group. In the pharmacokinetic study the median peak serum concentration occurred two hours after intake of tablets. The efficacy of double beta lactam treatment in lung infections with H. influenzae appears to be equivalent to that of ampicillin on clinical lung symptoms, lung function tests, adverse effects and bacteriology.     

The Preparation and Evaluation of a Tablet Dosage Form of Cyclosporine in Dogs

Cyclosporine (CsA) is commercially available for oral administration as a solution in olive oil with alcohol and an emulsifier. To improve its variable absorption and low patient acceptability, several oral formulations were prepared and tested in vitro and in vivo in dogs. A tablet formulation prepared by direct compression was then selected for comparison with the commercial oil solution placed into soft gelatin capsules. The study involved a randomized crossover design in six dogs. In order to determine absolute bioavailability and to compensate for any time-dependent changes in clearance, an intravenous tracer dose of ³H-CsA was administered along with each oral test product on each of two occasions. Absolute bioavailability (mean ± SD) was 46.0 ± 11.1 and 45.4 ± 9.9% for the capsules and tablets, respectively. C _max, t _max, and mean absorption time were not significantly different between the two products. No differences were observed in the pharmacokinetics of the intravenously administered CsA in the two experiments, which were separated by 8–13 days. We conclude that the proposed tablet formulation for CsA is equivalent in dogs to the commercial dosage form placed into soft gelatin capsules.     

Clinical pharmacokinetics and oral bioavailability of ketobemidone

Summary The basic pharmacokinetics and oral bioavailability of ketobemidone have been studied in 6 patients after surgery. Plasma concentrations were first determined following intravenous administration of Ketogin^® 2 ml, containing ketobemidone chloride 10 mg and the spasmolytic N,N-dimethyl-3,3-diphenyl-1-methylallylamine chloride 50 mg, and then, on the second postoperative day, following oral administration of 2 tablets of Ketogin^®, each containing ketobemidone chloride 5 mg and the spasmolytic agent 25 mg. The average oral bioavailability of ketobemidone was 34%±16% (SD, n=6). The mean plasma half-life of elimination (t_1/2) was about the same following oral (2.45±0.73 h; SD, n=5) as after intravenous administration (2.25±0.35 h; SD, n=6). The low oral bioavailability and rapid elimination of ketobemidone demonstrated in this study suggest that the usual dosage recommendation for oral Ketogin^® (ketobemidone 5–10 mg every 6–7 h) in patients with severe pain is too low.     

Evaluation of the Intestinal Absorption of Erythromycin in Man: Absolute Bioavailability and Comparison with Enteric Coated Erythromycin

To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 ± 0.08 (mean ± SD) hours and for the capsule was 2.92 ± 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 ± 7% and for the duodenal solution 43 ± 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 ± 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.     

Polyvinyl Alcohol–Methyl Acrylate Copolymers as a Sustained-Release Oral Delivery System

Low crystalline and crystalline polyvinyl alcohol–methyl acrylate (PVA-MA) copolymers were examined, because of their excellent flow and compressibility properties, as matrices for sustained-release tablets using phenylpropanolamine hydrochloride (PPA.HC1) as a model drug. Crystallinity of the copolymer affected the release characteristics from the tablet. Tablets made with low-crystalline PVA-MA provided sustained release of PPA, both in vitro and in vivo in dogs. PPA absorption from the low-crystalline PVA-MA tablet formulation was biphasic. An initial rapid phase was followed by a second, slower absorption phase which continued over 16 hr. Plasma PPA concentrations then declined with a half-life roughly parallel to the oral immediate-release half-lives. Oral bioavailability from the low-crystalline PVA-MA tablet formulation was 78.8 ± 3.9%.