1 Fosinopril sodium is the first phosphorus-containing angiotensin-converting enzyme (ACE) 3 After the intravenous dose of SQ 27, 519, the 0 to 96 h recovery of radioactivity averaged 44 and 46% of the dose in urine and faeces, respectively, indicating substantial biliary secretion. Only intact SQ 27, 519 was detected in the plasma, urine, and faeces following the intravenous dose of SQ 27, 519. 4 After oral doses of fosinopril sodium, about 75% of the radioactivity in plasma and urine was present as SQ 27, 519; the remainder corresponded mainly to a ,-glucuronide conjugate of SQ 27, 519 (15-20%), and a monohydroxylated analogue of SQ 27, 519 (about 5%). Negligible amounts of fosinopril sodium were present, indicating complete hydrolysis of the prodrug. 5 For the solution and capsule doses, respectively, the oral absorption of fosinopril sodium averaged 32% and 36% and the oral bioavailability of SQ 27, 519 averaged 25% and 29%. 6 The average values for clearance (39 ml min-1), renal clearance (17 ml min-1), Vss (10 1), and plasma protein binding (-95%), indicated that SQ 27, 519 was slowly cleared from the body and not distributed extensively into extravascular sites.
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 pharmacokinetics, pharmacodynamics, and safety of fosinopril sodium (SQ 28,555), a new orally active angiotensin-converting enzyme (ACE) inhibitor, was evaluated in 73 healthy men in two separate studies. In study I, doses ranging from 10 to 640 mg were administered once daily for 3 days to seven groups of five subjects each. Serum aldosterone levels, ACE activity, and sitting blood pressure were determined, as were pharmacokinetic parameters of fosinoprilat, the active diacid of fosinopril. In a dose-tolerance study (study II), 80 and 160 mg of the drug were administered in doses of 40 mg bid and 80 mg bid for 2 weeks. Pharmacokinetics were determined on days 1 and 14, and blood pressure and ACE activity were measured daily. One hour after all doses of fosinopril, serum ACE activity was undetectable. Peak blood levels of fosinoprilat occurred at about 3 hours after dosing, and linear kinetics of the diacid were observed. ACE activity remained undetectable for more than 24 hours after the treatment was stopped in study II. Serum aldosterone levels were decreased by 50% of baseline values in both studies. In study I, maximal reductions in mean blood pressure occurred approximately 6 hours postdose; once-daily doses of 20 mg or greater achieved reductions of 11.3 to 21.6% (P less than or equal to .05, compared with placebo reductions). Fosinopril was well tolerated. Subjects reported only mild gastrointestinal complications at doses of 80 mg/day or higher. These data show that fosinopril is a safe and effective inhibitor of ACE with a long duration of action on serum ACE activity.
Azthreonam is a new completely synthetic, monocyclic beta-lactam antibiotic with potent activity in vitro against most gram-negative aerobic bacteria. Its renal handling was studied in six healthy men after an intravenous loading dose of 1200 mg over 2 min followed by a continuous infusion of 500 mg/hr for 4 hr with and without oral probenecid (1 gm b.i.d. for 2 days before azthreonam infusion and during the day of infusion). To assess glomerular filtration, each subject also received an intravenous loading dose and continuous infusion of inulin. Azthreonam was excreted in the urine by glomerular filtration and tubular secretion in essentially equal proportions. Probenecid reduced plasma clearance of azthreonam bY suppressing renal tubular secretion, without altering glomerular filtration rate or nonrenal elimination. Probenecid increased total and free azthreonam levels and the azthreonam plasma t1/2 while reducing plasma protein binding and the apparent steady-state volume of distribution.
Serum and milk concentrations of aztreonam were studied in 12 lactating, healthy subjects over the 8 h period after the administration of a single intramuscular or intravenous 1 g dose. Milk concentrations of aztreonam were found to be much lower than serum concentrations at all time points after both routes of injection. Peak milk concentrations of aztreonam averaged less than 1% of peak serum concentrations. Times to peak concentrations averaged 6 and 10 times longer in milk than in serum after intramuscular and intravenous injections, respectively. The low milk levels, as well as the previously determined poor oral absorption of aztreonam, suggest a low risk of untoward effects in the nursing infant.
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