No abstract

The metabolism and pharmacokinetics of aztreonam (SQ 26,776) were studied in four healthy male volunteers, each of whom received single 500-mg intravenous and intramuscular doses of "4C-labeled drug according to a two-way crossover design. Serial The purpose of this study was to investigate further the metabolism and pharmacokinetics of aztreonam by using, for the first time, the radiolabeled drug administered both intravenously and intramuscularly to the same subjects. MATERIALS AND METHODSSubjects. Six healthy male subjects participated in this study; however, urine collections for two were incomplete. The latter two subjects were excluded from any further consideration in this report. The four remaining subjects had a mean age of 28 years (range, 21 to 30), mean height of 177 cm (range, 168 to 187), and mean weight of 73.3 kg (range, 69.2 to 80.1). All four subjects were considered healthy as determined by normal physical examination, 12-lead electrocardiogram, complete blood count, urinalysis, and serum chemistry proffle. None had a history of chronic disease, drug abuse, recent drug ingestion, or allergy to any drug or other substances. All of the subjects gave informed, written consent before entry into this study. The study protocol was approved by the Insti-

The concentrations of aztreonam in human tissues obtained during surgery were measured after a single 2-g intravenous dose. The average concentration in the skeletal muscle, atrial appendage, lung, sternum, pericardial fluid, endometrium, myometrium, fallopian tube, and ovary varied from 3 to 33 ,ug/g (or ,ug/mI). These concentrations significantly exceed the MIC for 90% of strains for most members of the family Enterobacteriaceae.Single parenteral doses of aztreonam produce significant concentrations in serum (14), cerebrospinal fluid (3, 5), bile (9), blister fluid (17), peritoneal fluid (16) Aztreonam assays. Skeletal muscle, atrial appendage, sternum, and lung tissue samples were minced into very small pieces and weighed. The sternum samples were pulverized with a Spex 6700 Freezer/Mill (Spex Industries, Metuchen, N.J.). The tissues were then diluted with 1 ml of 0.1 M phosphate buffer (pH 6.0) per g of sample. After dilution, the samples were homogenized for 1 min by using a Tekmar homogenizer (Tekmar, Cincinnati, Ohio). The homogenates were diluted with 3 ml of 50% methanol (in pH 6.0 phosphate * Corresponding author. buffer) per g of homogenate. The diluted homogenates were then centrifuged, and the supernatant was decanted and saved.The pellet was extracted twice with 5 ml of 30% methanol (in pH 6 phosphate buffer) per g of pellet. Filtered (Millex, 0.45-[im pore size; Millipore Corp., Bedford, Mass.) extracts were assayed by high-pressure liquid chromatography equipment that was previously described (11). Serum obtained simultaneously with thoracic tissues and fluids was assayed by a previously described high-pressure liquid chromatography method (11), and a similar method was used to assay pericardial and pleural fluid.Commercially obtained samples of tissue or body fluid (Agrilab Inc., Bridgewater, N.J.) were mixed with known amounts of aztreonam at the time the specimens were obtained from study patients. These spiked samples were assayed for aztreonam, and the results were used to correct clinical specimen assay results for losses during storage.The limit of detection, assay coefficient of variability, and recovery from spiked samples for each type of high-pressure liquid chromatography assay ranged from 0.5 to 1.3 ,ig/g (or jLg/ml), 5.3 to 14.7%, and 80.4 to 101%, respectively.Gynecologic tissue and simultaneous serum were assayed by microbiologic methods. The method for serum was previously described (14).Frozen tissue samples were thawed and cut into small pieces, and 0.2-g samples were weighed into a labeled test tube. These samples were refrozen at -78°C until assayed. On the day of assay, the samples were extracted by a procedure similar to that used for the high-pressure liquid chromatography assay of thoracic tissues.