Abstract
A 50-mg dose containing 50 µCi 14C-isomazole was administered orally to five healthy male volunteers. Blood, plasma, urine, feces, and saliva were collected and measured for total 14C; in addition, all collections except feces were measured for parent drug (ISO) and three metabolites: hydroxyisomazole (OHISO) and sulfone (SULF) and hydroxysulfone (OHSULF) analogues. Urine and fecal recoveries accounted for 97.0% of the drug administered, with 62.6% excreted in urine and 32.4% in feces. Only 47% of the drug recovered in urine could be identified, with ISO the largest constituent. Total plasma 14C peaked at 1.5 hr, indicating rapid absorption, and produced a mean half-life of 3.7 hr. This was similar to the total 14C half-life found in blood (3.1 hr) but longer than in red blood cells (1.8 hr) or saliva (1.4 hr), suggesting that different ISO-related compounds contributed to the results found in each fluid or tissue. An unidentified metabolite(s) composed a large portion of circulating plasma 14C and produced the longer half-life encountered in plasma. ISO exhibited a short half-life (1.35 hr), a high oral clearance (ClS/F; 24.2 ml/min/kg), and some extravascular distribution (Vβ; 3.07 L/kg). Total 14C in red blood cells and saliva related very well to plasma ISO disposition, suggesting preferential distribution of parent drug across cellular membranes. The estimated RBC:plasma ISO ratio (1.79) confirmed this hypothesis. Saliva may be used as a noninvasive means to monitor ISO disposition.
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REFERENCES
P. J. Cannon. A placebo controlled trial of captopril in refractory chronic congestive heart failure. J. Am. Coll. Cardiol. 2:755–763 (1983).
R. R. Miller, A. R. Palomo, B. S. Brandon, C. J. Hartley, and M. A. Quinones. Combined vasodilator and inotropic therapy of heart failure: experimental and clinical concepts. Am. Heart J. 102:500–508 (1981).
J. Cohn. Effect of vasodilator therapy on mortality in congestive heart failure. N. Engl. J. Med. 314:1547–1552 (1986).
J. S. Hayes, J. Bowling, G. D. Pollack, and D. W. Robertson. Roles for Ca++ and cyclic AMP in mediating the cardiotonic actions of isomazole (LY175326). J. Pharmacol. Exp. Ther. 237:18–24 (1986).
J. S. Hayes, G. D. Pollock, H. Wilson, N. Bowling, and D. W. Robertson. Pharmacology of LY175326: A potent cardiotonic agent with vasodilator activities. J. Pharmacol. Exp. Ther. 233:318–326 (1985).
J. R. Means, R. B. Franklin, and G. E. Sandusky. Toxicological evaluation of the cardiotonic isomazole in the dog. Fund. Appl. Toxicol. 13:418–428 (1989).
G. E. Sandusky, R. B. Franklin, and J. R. Means. Acute, sub-chronic, and chronic toxicity of the cardiotonic isomazole in rats. Fund. Appl. Toxicol. 13:409–417 (1989).
J. R. Bernstein and R. B. Franklin. In vivo reduction and reoxidation of isomazole: studies with 18O-labelled isomazole. Med. Sci. Res. 15:569–570 (1987).
J. R. Woodworth, A. F. DeLong, A. F. Fasola, and S. Oldham. Isomazole disposition as a function of dose and route of administration (accepted for publication Biopharm. Drug Dispos.).
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Woodworth, J.R., DeLong, A.F., Fasola, A. et al. 14C-Isomazole Disposition in Man After Oral Administration. Pharm Res 8, 1413–1417 (1991). https://doi.org/10.1023/A:1015857324838
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DOI: https://doi.org/10.1023/A:1015857324838