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 This review of the published and unpublished literature on cyclamate attempts to evaluate the carcinogenicity question and other important aspects of the toxicity of cyclamate and cyclohexylamine,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.
A series of renin inhibitors have been prepared and evaluated for their susceptibility to cleavage by the serine protease chymotrypsin. The compounds were designed by consideration of the structural requirements in the active-site region of renin and chymotrypsin. By systematic alteration of the P3 phenylalanine residue, compounds with varying degrees of renin inhibitory potency and chymotrypsin susceptibility were obtained. Selected analogues from this group were examined in vivo for both their hypotensive effects and metabolic patterns.
1 Serum and urine concentrations of enantiomers of pazinaclone (DN-2327) and an active metabolite Ml,, were measured after single and twice daily oral doses of 4 and 8 mg racemic drug to healthy subjects.2 The kinetics of rac-pazinaclone and rac-MI, were dose-independent and no unchanged drug was recovered in urine. 3 The terminal elimination half-lives of the drug isomers were similar (about 10.5 h), but mean steady-state values of AUC were twofold higher for the S-isomer than those of the antipode (e.g., 8 mg dose: 127 vs 69 ng ml-' h). However, the corresponding AUC values based upon unbound drug were similar (5.71 vs 5.73 ng ml-h) indicating no stereoselectivity in intrinsic metabolic clearance.4 The terminal elimination half-lives of S-and R-MI, were similar to those of parent compound indicating that the elimination of these metabolites is formation ratelimited.5 The R:S-ratio for the AUCs of MI, was 4:1. Both enantiomers were excreted in the urine mainly as glucuronide conjugates, with stereoselectivity toward S-Mll. 6 Since only the S-enantiomers of DN-2327 and MI, bind to the benzodiazepine receptor, further measurements of drug effect in patients should be related to combine serum concentrations of the S-enantiomers of both parent drug and Ml,.
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