The metabolic fate of the orally effective cephalosporin antibiotic cefaclor (Lilly 99638) has been studied in rats, mice, and dogs. Cefaclor is efficiently absorbed from the gastrointestinal tract as the intact antibiotic. In rats and mice, cefaclor, for the most part, escapes metabolism in the body and is eliminated unchanged as unaltered antibiotic, primarily by renal excretion. In dogs, however, cefaclor is more labile to metabolism and only a portion ofthe administered antibiotic is eliminated unchanged via the kidney.Cefaclor (see Fig. 1), 3-chloro-7-D-(2-phenylglycinamido)-3-cephem-4-carboxylic acid (Lilly 99638), is an orally effective, broad-spectrum antibiotic active against gram-positive cocci, including penicillin-resistant strains, as well as against many gram-negative organisms. Cefaclor is a cephalosporin antibiotic structurally related to orally active cephalexin [generic name given to 7-(D>2-amino-2-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid] (6). The study described below, which is patterned after earlier studies (1,(7)(8)(9), shows that cefaclor is well absorbed after oral administration and that this antibiotic is, like cephalexin, resistant to metabolic degradation or alteration. As in earlier studies on the in vivo fate of cephalosporin antibiotics from these laboratories, radiocarbon labeling was used to facilitate the present investigation.
MATERIALS AND METHODS['4C]cefaclor. D_[1-'4C]phenylglycine (1.59 mmol, 20.86 1&Ci/mg) was allowed to react with 2.06 mmol of methyl acetoacetate in a solution of 1.62 mmol of NaOH in 15 ml of methanol. After heating the reaction mixture for 1.5 h at reflux temperature, 15 ml of acetonitrile was added and heating was continued for 30 min. Methanol was removed by distillation and was replaced with an appropriate a,mount of acetonitrile. After cooling to room temperature, the chloro-3-cephem-4-carboxylate in 5 ml of dimethylformamide was added rapidly with stirring. The resulting mixture was stirred at -40°C for 2.5 h and then was allowed to stand overnight at room temperature. Upon cooling the mixture to 0°C, water (0.5 ml) and then 0.9 ml of concentrated HCI was added dropwise. Zinc dust (5.46 mmol) was added to the reaction mixture over a period of 30 min, keeping the temperature between 0 and 5°C. After complete addition, the reaction mixture was stirred at 0°C for 2.5 h. Concentrated HCl (0.56 ml) was then added, and stirring was continued for 1 h. The pH of the reaction mixture was then adjusted from 1.6 to 3.5 with triethylamine and filtered. Semicarbazide -hydrochloride (1.44 mmol) was added portionwise to the filtrate over a period of 30 min, maintaining the pH at 3.5 with triethylamine. After complete addition, the pH of reaction solution was adjusted to 6.8 with stirring in an ice bath to facilitate precipitation. The crude product was collected by filtration, washed with dimethylformamide, and then dissolved in a solution containing 9.3 ml of water, 0.12 ml of concentrated HCl, and tetrasodium ethylenediaminetetraacetate dihydrate (0...