In vitro pharmacodynamic parameters of sordarin derivatives in comparison with those of marketed compounds against Pneumocystis carinii isolated fromrats

Pneumocystis carinii pneumonia remains one of the most serious complication s of immunosuppressed patients. In this study, the in vitro pharmacodynamic parameters of four sordarin derivatives (GM 191519, GM 237354, GM 193663, and GM 219771) have been evaluated by a new quantitative approach and compa red with the commercially available drugs pentamidine, atovaquone, and trim ethoprim-sulfamethoxazole (TMP-SMX). In vitro activities and in vivo therap eutic efficacies of sordarin derivatives against P. carinii were also evalu ated. In vitro activity was determined by the broth microdilution technique , comparing the total number of microorganisms in treated and drug-free cul tures by using Giemsa staining. The in vitro maximum effect (E-max), the dr ug concentrations to reach 50% of E-max (EC50), and the slope of the dose-r esponse curve were then estimated by the Hill equation (E-max sigmoid model ). Sordarin derivatives were the most potent agents against P. carinii, wit h EC(50)s of 0.00025, 0.0007, 0.0043, and 0.025 mu g/ml for GM 191519, GM 2 37354, GM 193663, and GM 219771, respectively. The EC(50)s of pentamidine, atovaquone, and TMP-SMX were 0.025, 0.16, and 26.7/133.5 mu g/ml, respectiv ely. The results obtained with this approach showed GM 237354 and GM 191519 to be approximately 35- and 100-fold more active in vitro than pentamidine , the most active marketed compound. All sordarin derivatives tested were a t least 5,000-fold more active in vitro than TMP-SMX. The three sordarin de rivatives tested in vivo-GM 191519, GM 237354, and GM 219771-showed a marke d therapeutic efficacy, defined as reduction of cyst forms per gram of lung . GM 191519 was the most potent (daily dose reducing 50% of the P. carinii burden in the lungs [ED50], 0.05 mg/kg/day) followed by GM 237354 and GM 21 9771 (ED(50)s, 0.30 and 0.49 mg/kg/day, respectively). Good agreement betwe en in vitro parameters and in vivo outcome was obtained when P. carinii pne umonia in rats was treated with sordarin derivatives.