The pharmacokinetics and safety of single ascending doses of clarithromycin (6-0-methylerythromycin A) were assessed in a placebo-controlled, double-blind, randomized trial with 39 healthy male volunteers. Subjects were randomized to receive single doses of either placebo or 100, 200, 400, 600, 800, or 1,200 mg of clarithromycin. Blood and urine collections were performed over the 24 h following administration of the test preparation. Biological specimens were analyzed for clarithromycin and 14(R)-hydroxyclarithromycin content by a high-performance liquid chromatographic technique. The pharmacokinetics of clarithromycin appeared to be dose dependent, with terminal disposition half-life ranging from 2.3 to 6.0 h and mean ± standard deviation area under the concentration-versus-time curve from time 0 to infinity for plasma ranging from 1.67: 0.48 to 3.72 t 1.26 mgtliter. h per 100-mg dose over the 100-to 1,200-mg dose range. Similar dose dependency was noted in the pharmacokinetics of the 14(R)-hydroxy metabolite. Mean urinary excretion of clarithromycin and its 14(R)-hydroxy metabolite ranged from 11.5 to 17.5% and 5.3 to 8.81% of the administered dose, respectivety. Urinary excretion data and plasma metabolite/parent compound concentration ratio data suggested that capacity-limited formation of the active metabolite may account, at least in part, for the nonlinear pharmacokinetics of darithromycin. No substantive dose-related trend was observed for the renal clearance of either compound. There were no clinically significant drug-related alterations in laboratory and nonlaboratory safety parameters. In addition, there was no significant difference between placebo and clarithromycin recipients in the incidence or severity of adverse events. Clarithromycin appears to be safe and well tolerated.The new 14-membered macrolide antimicrobial agent clarithromycin (A-56268, TE-031) is active in vitro against several important gram-positive and gram-negative pathogens, such as Streptococcus pyogenes, Staphylococcus aureus, Haemophilus species, Legionella species, Mycobacterium avium complex, and Chlamydia species (2, 4, 6, 8-10, 16, 19). Clarithromycin is active intracellularly, and its action is static or bactericidal, depending on the organism and antimicrobial agent concentration (2). Clarithromycin is more acid stable than erythromycin and in animal models achieves higher concentrations in plasma and tissue than erythromycin, especially in the lung (12, 13,15). The Food and Drug Administration-approved dosage regimen for clarithromycin ranges from 250 to 500 mg twice daily (respiratory tract and skin or skin structure infections).The present study was designed to assess the pharmacokinetics and safety of oral clarithromycin in a single-ascending-dose study in healthy young adult male volunteers.( graphy, and audiometry criteria. No subjects were receiving chronic medication.The study was approved by the Institutional Review Board of Quincy Research Center, Kansas City, Mo., and all subjects provided written, informed...

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In the late 1960s the artificial sweetener cyclamate was implicated as a bladder carcinogen in rats. This finding and other concerns about its safety ultimately led to a ban on cyclamate in the U.S. and restrictions on its use in many other countries. Since that time, the carcinogenic potential of cyclamate and cyclohexylamine, its principal metabolite, has been reevaluated in a group of well-controlled, well-designed bioassays that have failed to substantiate the earlier findings. This review of the published and unpublished literature on cyclamate attempts to evaluate the carcinogenicity question and other important aspects of the toxicity of cyclamate and cyclohexylamine, including their effects on various organ systems, their genotoxic potential, and their effects on reproduction. In addition, the physiological disposition of cyclamate is reviewed, with particular attention directed toward the site and extent of its conversion to cyclohexylamine.