The biliary excretion of 18 cephalosporin derivatives with varying 3-and 7-substituents was examined in cannulated rats. In spite of the widely differing physical chemical properties imparted by the different structures, the dominant influence on the degree of biliary excretion was the molecular weight of the compound. Above a threshold molecular weight of about 450, biliary excretion increased in a generally progressive way, becoming the principal route of excretion of the higher-molecular-weight derivatives. Examples were found in which the molecular weight influence was modified but not abolished by specific substituents. Biliary excretion varied from less than 5% to greater than 90% of the dose. Interruption of bile flow resulted in an increase in urinary excretion. Biliary excretion may influence the evaluation of new cephalosporins in rodent models. Such influence must be considered when selecting candidate compounds intended for eventual use in humans, where the excretion pattern may be different from that in rodents.Molecular weight is known to influence the degree of biliary excretion of some classes of compounds (4,7,8). Since cephalothin (molecular weight, 396) was introduced into medicine in 1964, many cephalosporin derivatives have been made in efforts to expand the antibacterial spectrum and improve the pharmacokinetic properties of this class of antibiotics. In recent years these modifications have sometimes resulted in derivatives having substantially higher molecular weights, as more complex structures were attached to the 3 and 7 positions of the cephem nucleus. Thus, we anticipated an increase in the fraction of the dose of highermolecular-weight cephalosporins to appear in the bile of rodent species used in early in vivo testing. Because we felt that such a change in biliary excretion might have important pharmacokinetic and distribution effects not previously seen with most cephalosporins, we examined the effect of molecular weight and other properties on the excretion of cephalosporins in the bile of cannulated rats.MATERIALS AND METHODS Cephalosporin derivatives. The 18 cephalosporins studied were chosen for their range of molecular weights (347 to 695), availability, and freedom from significant metabolism. Some are commercially available; the rest were prepared over the course of several years in the Chemical Research Division of Eli Lilly and Co. as candidates in a number ofstructure-activity studies. Their structures are shown in Table 1 and are identified by generic name or Lilly compound number.Before their use in this study, all of these derivatives had undergone preliminary animal evaluation as potentially useful antibiotics. On the basis of these evaluations, which usually included both chromatographic analysis of bile and urine and bioactivity balance in vivo, the derivatives shown in Table 1 were judged to be acceptable for this kind of study. All except two of the derivatives were recoverable in combined bile and urine at greater than 80% of the dose, and most were greater than...

Medical examiners frequently rely on the finding of free morphine present in postmortem specimens to assist in certifying deaths associated with narcotics. In vitro hydrolysis of morphine-3-D glucuronide (M3DG) to free morphine was studied using variable specimen pH, initial degree of specimen putrefaction, storage temperature and time, and the effectiveness of sodium fluoride (NaF) preservation. Reagent M3DG was added to opiate-free fresh blood and urine and to autopsy-derived blood specimens. Reagent bovine glucuronidase was also added to certain specimens. Freshly collected and refrigerated NaF-preserved blood produced minimal free morphine, whereas four of five autopsy blood specimens produced free morphine from M3DG. Increased storage time, temperature, and initial degree of putrefaction resulted in greater free morphine generation despite the absence of viable bacteria. Hydrolysis occurring during specimen storage can generate free morphine from M3DG and may result in erroneous conclusions in certifying narcotic deaths.

The synthesis of six amino acid acyloxymethyl esters of cefamandole (1), a semisynthetic broad-spectrum cephalosporin antibiotic, is described. These esters were examined as potentially useful orally active antibiotic prodrugs. When tested for oral efficacy against Streptococcus pyogenes C203 in mouse protection tests, the esters were not notably more active than lithium cefamandole. Further studies demonstrated that significant blood and urine levels of 1 were not obtained after dosing 2a, 2b, and 2f orally at 17 mg/kg in mice. A study of the stability to chemical hydrolysis and the possible relationship of hydrolysis to the lack of oral absorption of these esters is also presented.

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