Abstract Acute Cardiotoxicity of the Anti-HIV Dideoxynucleoside, F-ddA, in the Rat. Donzanti, B. A., Kelley, J. A., Tomaszewski, J. E., Roth, J. S., Tosca, P., Placke, M., Singer, A., Yarrington, J. T., and Driscoll, J. S. (1995). Fundam. Appl. Toxicol. 27, 167-176. 2′-β-Fluoro-2′,3′-dideoxyadenosine (F-ddA), an acid-stable, purine dideoxynucleoside with in vitro anti-HIV activity, has been selected by the NCI as a clinical trial candidate. A recent report that high, single doses of F-ddA produce cardiotoxicity in rats prompted the present investigation whose objective was to quantitate this effect and establish a relationship between this toxicity and F-ddA plasma concentrations. Microscopic examination of cardiac tissues for degenerative lesions established the effects of F-ddA and ddA on three iv schedules [daily × 1 (2.5-250 mg/kg); daily × 5 (125, 250 mg/kg), and BID × 1 (250 mg/kg)] as well as one oral schedule [BID × 1 (500 mg/kg)] using 8- to 12-week-old female Sprague-Dawley rats. For both F-ddA and ddA, the group mean severity of the cardiac lesions was dose-dependent and proportional to the measured plasma concentrations of the undeaminated parent drugs. F-ddI and ddI, the respective deaminated catabolites of F-ddA and ddA, were essentially nontoxic in this study (iv, 250 mg/kg, daily × 1 and daily × 5), since plasma concentrations exceeding 2 mM produced only minimal cardiac lesions. The cardiomyopathy of F-ddA was minimal to mild for all iv doses except 250 mg/kg (daily × 1) and usually was greater than that of ddA at any given dose. This is a consequence of the fact that F-ddA is deaminated 20 times more slowly than ddA, resulting in higher plasma concentrations of F-ddA relative to ddA at any given time for any given dose. Neither F-ddA nor ddA was more cardiotoxic on a repeated iv schedule (daily × 5) than when administered only once, suggesting that rat cardiotoxicity is related to C max rather than total exposure. In this most sensitive species, the formation of cardiac lesions above the background level is associated with iv F-ddA administration when the F-ddA plasma concentration approaches 300 μM, 30-50 times the anticipated therapeutic level in humans.