PHARMACOKINETICS OF PENTOXIFYLLINE AND ITS METABOLITES IN HEALTHY MICE AND IN MICE INFECTED WITH CANDIDA-ALBICANS

Pentoxifylline has immunomodulatory properties and has been shown to d ecrease organ damage and improve survival in animals with gram-negativ e sepsis or endotoxemia. This effect is mediated by a reduction in end otoxin-induced production of tumor necrosis factor alpha (TNF-alpha) b y the host. In earlier studies, we observed an unexpected increase in mortality id mice infected with Candida albicans that were given pento xifylline even though concentrations of TNF-alpha in serum were not Ef fected. The current study was designed to determine whether the pharma cokinetics of pentoxifylline and its metabolites were altered in C. al bicans-infected mice and, if so, whether these changes could have cont ributed to the increased mortality, Noninfected mice and mice infected with C, albicans were treated with pentoxifylline (60 mg/kg of body w eight) intraperitoneally every 8 h, Serum was collected from animals a fter one (day ii), four (day 1), or seven (day 2) injections of pentox ifylline or saline (controls). The first dose was administered 6 h aft er C. albicans infection. Serum was pooled. Concentrations of pentoxif ylline and metabolites I, IV, and V were determined by capillary gas c hromatography. Renal function and hepatic profiles were assessed. Phar macokinetic parameters (maximum concentration of pentoxifylline in ser um, half-life, and area under the concentration-time curve from 0 h to infinity [AUC(0-infinity)]) for all noninfected mice were similar and did not differ from those for day 0-infected mice. For day I-infected mice, values of these three pharmacokinetic parameters for pentoxifyl line and metabolite I were increased two- to fourfold over values for noninfected and day 0 infected mice. For metabolites IV and V, the AUG ,, was increased approximately eightfold over control values, In addit ion, day 1-infected mice demonstrated evidence of renal and hepatic dy sfunction. In summary, C. albicans infection produced marked changes i n the pharmacokinetics of pentoxifylline and its metabolites in the mi ce. The high concentrations of pentoxifylline and its metabolites in s erum attained in infected mice may have contributed to the increased m ortality of mice with systemic candidiasis.