Penicillins elimination

Another issue of relevant importance to the interpretation of analytical results is the analytical specificity of the test, particularly when in an immunobased assay. Specificity is exquisite in immunochemical assays but, at the same time, it can be exquisitely troublesome. For example, when an immunochemical assay for the penicilloyl group is used to monitor the pharmacokinetics of penicillin elimination from the serum of treated animals, the measured levels remain high for at least several weeks, although the antibacterial activity was all eliminated from bovine serum within 24 h after injection. This is because the immunochemical assay measured not only the free drug but also the penicilloyl groups covalently bound to proteins in serum. The half-life of these bound residues is roughly equal to the half-life of the proteins in the circulation. 

Many principles of antibiotic selection are illustrated by this patient. (1) His history of serious allergy to penicillin eliminated this entire family of antibiotics from consideration. Thus, when his dental abscess... 

Isolation. Isolation procedures rely primarily on solubiHty, adsorption, and ionic characteristics of the P-lactam antibiotic to separate it from the large number of other components present in the fermentation mixture. The penicillins ate monobasic catboxyHc acids which lend themselves to solvent extraction techniques (154). Pencillin V, because of its improved acid stabiHty over other penicillins, can be precipitated dkecdy from broth filtrates by addition of dilute sulfuric acid (154,156). The separation process for cephalosporin C is more complex because the amphoteric nature of cephalosporin C precludes dkect extraction into organic solvents. This antibiotic is isolated through the use of a combination of ion-exchange and precipitation procedures (157). The use of neutral, macroporous resins such as XAD-2 or XAD-4, allows for a more rapid elimination of impurities in the initial steps of the isolation (158). The isolation procedure for cephamycin C also involves a series of ion exchange treatments (103). 

One of the major differences between penicillins and cephalosporins is the possibility for a concerted elimination of the C-3 substituent in the case of cephalosporins (6->7). There is now considerable evidence to support the idea that an increase in the ability of the C-3 substituent to act as a leaving group results in an increased reactivity of the 8-lactam carbonyl (75JMC408). Thus, both the hydrolysis rate of the 8-lactam and antibacterial activity... 

The importance of the penicillins as a class of heterocyclic compounds derives primarily from their effectiveness in the treatment of bacterial infections in mammals (especially humans). It has been estimated that, in 1980, the worldwide production of antibiotics was 25 000 tons and, of this, approximately 17 000 tons were penicillins (81MI51103). The Food and Drug Administration has estimated that, in 1979 in the U.S.A., 30.1 x 10 prescriptions of penicillin V and 44.3 x 10 prescriptions of ampicillin/amoxicillin were dispensed. This level of usage indicates that, compared to other methods of dealing with bacterial infection, the cost-benefit properties of penicillin therapy are particularly favorable. Stated differently, penicillin treatment leads to the elimination of the pathogen in a relatively high percentage of cases of bacterial infection at a relatively low cost to the patient in terms of toxic reactions and financial resources. 

We also wanted to evaluate the disassembly of our dendritic system under physiological conditions. Thus, we synthesized a self-immolative AB6 dendron 32 with water-soluble tryptophan tail units and a phenylacetamide head as a trigger (Fig. 5.26) to evaluate disassembly in aqueous conditions. The phenylacetamide is selectively cleaved by the bacterial enzyme penicillin G amidase (PGA). The trigger was designed to disassemble through azaquinone methide rearrangement and cyclic dimethylurea elimination to release a phenol intermediate that will undergo six quinone methide elimination reactions to release the tryptophan tail units. 

HPCE separations utilizing the MEKC mode allow the electrophoretic separations of neutral components using detergent micelles. The advantage of using detergents is that in most cases the sample cleanup and solubilization step can be eliminated because of the presence of the detergent. Penicillins,112113... 

The dose of aciclovir in patients with renal impairment should be reduced as aciclovir is eliminated by the renal system. Most penicillins are eliminated by the renal system and hence dose reduction of amoxicillin is required in cases of renal impairment. Non-steroidal anti-inflammatory drugs cause the inhibition of the biosynthesis of prostaglandins involved in the maintenance of renal blood flow. This may precipitate acute renal insufficiency in patients with renal impairment. Furthermore non-steroidal anti-inflammatory drugs tend to cause water and sodium retention and hence aggrevate renal impairment. 

The absorption and excretion of carbenicillin in man has been reported [396]. The antibiotic is not absorbed intact from the gut intramuscular injection (which is painful) often provides adequate serum levels (approximately 20 Mg/ntl) but infections with Pseudomonas strains having minimum inhibitory concentrations up to, or higher than, 100 Mg/ml require intravenous thbrapy to achieve such levels. No evidence of active metabolite formation has been obtained. Marked reductions in the half-life (and serum levels) of carbenicillin follow extracorporeal dialysis or peritoneal dialysis, the former producing the most striking effect [397]. These results were, of course, obtained in patients with severe renal failure. Patients with normal renal function rapidly eliminate the drug but, as with all penicillins, renal tubular secretion can be retarded by concurrent administration of probenecid. 

The dose dependence of the time course of the drug effect is exploited when the duration of the effect is to be prolonged by administration of a dose in excess of that required for the effect. This is done in the case of penicillin G (p. 268), when a dosing interval of 8 h is being recommended, although the drug is eliminated with a half-life of 30 min. This procedure is, of course, feasible only if supramaximal dosing is not associated with toxic effects. 

Penicillin G undergoes rapid renal elimination mainly in unchanged form (plasma ti/2 - 0.5 h). The duration of the effect can be prolonged by ... 

Combination with probenecid. Renal elimination of penicillin occurs chiefly via the anion (acid)-secretory system of the proximal tubule (-COOH of 6-APA). The acid probenecid (p. 316) competes for this route and thus retards penicillin eUmination ... 

Excretion - Penicillins are excreted largely unchanged in the urine by glomerular filtration and active tubular secretion. Nonrenal elimination includes hepatic inactivation and excretion in bile this is only a minor route for all penicillins except nafcillin and oxacillin. Excretion by renal tubular secretion can be delayed by coadministration of probenecid. Elimination half-life of most penicillins is short (no... 

Some penicillins cannot be given orally as their beta-lactam ring is hydrolyzed and inactivated in the stomach by gastric acid. In general intramuscular injections are painful and therefore not advised. The pharmacokinetic behavior of penicillins is further characterized by short elimination half-lives. Renal elimination is prominent. 

Renal elimination of foreign compounds may change dramatically with increasing age by factors such as reduced renal blood flow, reduced glomerular filtration rate, reduced tubular secretory activity, and a reduction in the number of functional nephrons. It has been estimated that in humans, beginning at age 20 years, renal function declines by about 10% for each decade of life. This decline in renal excretion is particularly important for drugs such as penicillin and digoxin, which are eliminated primarily by the kidney. 

Penicillin G is excreted by the kidneys, with 90% of renal elimination occurring via tubular secretion and 10% by glomerular filtration. Probenecid blocks tubular secretion and has been used to increase the serum concentration and prolong the half-life of penicillin G and other penicillins. Additional pharmacokinetic information can be found in Table 45.1. 

The antipseudomonal penicillins undergo renal elimination (Table 45.1). Piperacillin and ticarcillin have minimal hepatic metabolism. In contrast, mezlocillin has significant hepatic metabolism and requires dose adjustment in patients with hepatic insufficiency. 

Semisynthetic heterocycles are also important dmg molecules. These compounds attempt to capture the best of both worlds, being synthetic derivatives of natural products. The use of a natural product in the preliminary stages of the synthesis enables the elimination of numerous costly synthetic steps. The subsequent synthetic modifications enable further fine tuning of the natural product pharmacophore. There are a number of semisynthetic penicillin derivatives available. Similarly, there are also semisynthetic hormone analogs, especially of estrogens and gestagens. 

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