Bioavailability of Bacampicillin and Talampicillin, Two Oral Prodrugs of Ampicillin

Abstract

A 200-mg amount of bacampicillin showed a significantly higher relative extent of bioavailability than did a 250-mg amount of talampicillin, possibly due to their different stability in the digestive juices.The prodrug technique is increasingly recognized as an approach to obtaining maximnum systemic concentrations in the body by the oral route (2). Several prodrugs of ampicilhin, such as bacampicillin, pivampicilhin, and talampicillin, have been made. The pharmacokinetics of bacampicillin and pivampicillin were compared in a previous report (8). The purpose of the present study was to compare the bioavailabilities of bacampicillin and talampicillin.The study was conducted in 10 male volunteers, 22 to 41 (mean 31) years old, with body weights ranging from 64 to 91 (mean 76) kg. All were healthy, as evidenced by routine clinical and laboratory examinations, and without known allergy to penicillins or cephalosporins. Before and after study, tests relevant to the renal and liver function, as well as hematological findings, were within normal ranges. Each subject received either a 200-mg (batch F162) or a 400-mg (batch F199) dose of bacampicillin hydrochloride (Penglobe; Astra Lakemedel AB, Sweden) or a 250-mg dose (batch 3902/A) of talampicillin hydrochloride (Talpen; Beecham Research Laboratories, England) in randomized order according to a complete crossover design with 1 week between experiments. After an overnight fast, the drugs were administered under supervision as single doses with 100 ml of water. Food was withheld for 3 h after medication. Intake of water was permitted ad libitum, except during the last hour before and the first hour after medication. The volunteers were instructed not to take any other drugs during the study. The study was approved by a peer review committee, and written informed consent was obtained.Blood samples were drawn from an antecubital vein before drug intake and 20 and 40 min, 1, 1.5, 2, 4, 6, and 8 h postmedication. Urine was collected at 2-h intervals during 8 h. All samples were stored at -20°C until analyzed. The ampicillin concentrations were determined by the cylinder-plate method, with Micrococcus luteus as test species (7). The detection limit in serum was 0.03 mg/liter. The relative extent of bioavailability was estimated by comparing the areas under the serum concentration versus time curves (AUC), calculated by the trapezoidal rule. A 200-mg amount of bacampicillin was used as standard in each subject. Areas were corrected for dose differences, calculated as anhydrous ampicillin. To test for significant differences in pharmacokinetic variables between drugs and doses (at the 5% level), the nonparametric Friedman analysis of variance was applied, followed by multiple comparisons based on the Friedman rank sums (3).None of the preadministration samples showed antibacterial activity. Both drugs were rapidly absorbed. The median time from tablet administration to the occurrence of the peak serum level was the same for all three doses, 40 min. The curves after 200 mg of b...

Age-related modifications in CYP-dependent drug metabolism: role of stress

“…It should be noted that several active metabolic products may have the potential to induce toxic manifestations including cell death, oxidative stress, tumor initiation and teratogenesis, among others ( 4 , 19 , 20 , 23 – 26 ). There are also inactive or weakly active drugs called pro-drugs, which are converted to pharmacologically active metabolites within the body through metabolic reactions predominantly catalyzed by cytochromes ( 8 , 19 , 27 – 30 ).…”

Stress as a Potential Regulatory Factor in the Outcome of Pharmacotherapy

“…Accordingly, pro-drugs are converted into pharmacologically active forms through metabolic activation that is mainly catalyzed by cytochromes (Chen et al, 2004 ; Gonzalez, 2005 ). This category of clinically important drugs include levodopa, talampicillin, cyclophosphamide, ftorafur, diazepam, prednisone, protonsil and enalapril, which are converted to dopamine, ampicillin, phosphoramide mustard, fluorouracil, oxazepam, prednisolone, sulfanilamide and enalaprilat, respectively (Sjovall et al, 1981 ; Chen et al, 2004 ; Rooseboom et al, 2004 ; Sozio et al, 2012 ; Konstandi, 2013 ).…”