EXTH-35. STEADY STATE BRAIN EXTRACELLULAR FLUID AND PLASMA PHARMACOKINETICS OF LETROZOLE IN SPRAGUE DAWLEY RATS: GENDER DIFFERENCES AND PROJECTIONS FOR TUMORAL DRUG LEVELS

摘要

Our recent studies indicate that aromatase, a cytochrome P450 (CYP) enzyme (CYP19A1), which catalyzes the conversion of androgens to estrogens, may be a novel druggable target for the treatment of high-grade gliomas (HGG). Additionally, letrozole, a potent aromatase inhibitor, exhibited marked activity against C6 glioma in Sprague-Dawley rats. Here, we conducted extensive single dose and steady state plasma and brain extracellular fluid (ECF) pharmacokinetics (PK) of letrozole in both female and male rats to facilitate further evaluation of its anti-HGG efficacy. We employed age-matched (65–74 days) adult female (200–225 g; N = 13) and male (300–325 g; N = 12) jugular vein cannulated Sprague-Dawley rats. Letrozole (4mg/kg) was administered intraperitoneally daily for 5–10 days. Serial blood and ECF samples (using intracerebral microdialysis) were collected and letrozole was quantitated employing an HPLC method. Marked gender-dependent difference in letrozole PK were observed with both plasma and brain ECF levels being markedly higher in female rats relative to those in male rats. For instance, the steady state peak plasma and ECF letrozole levels in female rats were 4.8 µg/ml and 2.3 µg/ml, respectively. For male rats, the corresponding values were 1.0 and 0.5 µg/ml. Likewise, the steady state plasma and brain ECF area under the curve (AUC) values were 4–5 fold higher in female rats. The steady state terminal half-life (t1/2) in female rats was markedly higher (36 ± 2 h), relative to that in male rats (13 ± 3 h). A preliminary assessment of the letrozole levels in C6 tumors excised 25 days post implantation indicated that the steady state tumor levels were in the range of 4–10 µg/g of tumor tissue. These results are facilitating dose optimization for further pre-clinical pharmacology and toxicology assessments. In addition, PK-modeling based projections will aid initial dose determination in future clinical studies.