Hetacillin

Latentiation of ampicillin can also be achieved by tying up the proximate amino and amide functions as an acetone aminal. Inclusion of acetone in the reaction mixture allows 6-APA to be condensed directly with the acid chloride from 24. There is thus obtained directly the prodrug hetacillin (34). Although this compound has little antibiotic activity in its own right, it hydrolyzes to ampicillin in the body. The p-hydroxy derivative amoxycillin (35) shows somewhat better oral activity. A similar sequence using formaldehyde gives metampicillin (36). °... 

Alprenolol HCl Bromelain Ciprofibrate Clortermine HCl Desonide Fenofibrate Flucloronide Flunisolide Fluocinonide Flurandrenolide Glucagon Gramicidin Hetacillin potassium I proniazid Kebuzone Methyltestosterone Niaprazine Probucol Relaxin Somatotropin Triamcinolone acetonide Acetonitrile... 

Fig. 5.14. Degradation of the ampicillin prodrug hetacillin (5.42). In an alkaline medium, Pathway a (epimerization at C(6)) is more important than Pathway b (hydrolysis producing... 

Penicillins. This group includes penicillin G (benzyl-penicillin), penicillin VK (phenoxymethyl-penicillin), the isoxazolyl penicillins oxacillin, cloxacillin, dicloxacillin and nafcillin, the amino-penicillins ampicillin, hetacillin and amoxycillin, the carboxy-penicil-lin carbenicillin, and the thienyl-penicillin ticarcillin. 

Hetacillin is a semisynthetic prodrug of ampicillin also inactivated by -lactamases. It is more stable in the gastric acid than ampicillin and amoxicillin and, therefore, is absorbed best. Hetacillin is inactive per se, but after it enters the bloodstream it is metabolized to ampicillin and becomes active. 

Prodrugs are drug substances that are biotransformed in the body to active metabolites and chemotherapeutic agents. Examples include sulfasalazine to sul-fapyridine, phenylbutazone to oxy-phenbutazone, aspirin to salicylate, and heta-cillin to ampicillin. In some cases, such as aspirin (ester) and hetacillin (amide), hydrolysis in water releases the active drug moiety contained within the basic structure of the prodrug. 

To 100 grams of a-aminobenzylpenicillin slurried in 2,500 ml of acetone is added 200 ml of a 22% solution of potassium ethylhexanoate in dry n-butanol and the mixture is warmed to 45°C whereupon the acid dissolves. After the mixture is agitated for 1 hour at 40° to 45°C, the product begins to crystallize out. Agitation is continued for 4 hours at 45°C after which the product, the potassium salt of hetacillin, is collected by filtration, washed with 500 ml of dry acetone, dried for 17 hours at 40°C and found to weigh 70.0 grams. 

---