Galocitabine

Capecitabine is an oral fluoropyrimidine carbamate which is converted to 5-fluorouracil (5-FU) via 3 enzymatic step to 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and finally 5-FU. We performed 4-week toxicity studies of capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorouridine), galocitabine (trimethoxybenzyl-5'-deoxy-5-fluorocytidine), 4 different fluoropyrimidine carbamate analogs (R=butyl, isopentyl, propyl, or phenethyl), and 5'-DFUR in cynomolgus monkeys with toxicokinetic measurements of intact molecules, 5'-DFCR, and 5'-DFUR. Four-week toxicity data for capecitabine in rats and mice were also obtained for comparison. Capecitabine, galocitabine, butyl, and isopentyl analogs showed similar toxicities in hematopoietic and intestinal organs at 1.0 mmol/kg and the AUCs of 5'-DFUR were approximately 40 to 60 microg*hr/ml. These compounds showed slight toxicity at 0.5 mmol/kg and no toxicity at 0.1 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 5 microg*hr/ml, respectively. Propyl and phenethyl analogs showed slight toxicity at 1.0 mmol/kg and no toxicity at 0.5 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 10 microg*hr/ml, respectively. On the other hand, severe and slight-to-moderate toxicity was observed at 0.5 and 0.25 mmol/kg in 5'-DFUR-treated monkeys and AUCs of 5'DFUR were 35.6 and 5.2 microg*hr/ml, respectively. In mice and rats, the toxicity of capecitabine was less than in monkeys relative to dose, but 5'-DFUR AUCs were almost the same. In conclusion, 5'-DFUR AUC correlated with toxicity following oral administration of capecitabine and its analogs in monkeys, mice, and rats, although this relationship is not seen in humans. Capecitabine was less toxic in monkeys than oral 5'-DFUR according to dose (mmol/kg) and 5'-DFUR AUC.

N4-Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine (Ro 09-1390) and 5'-deoxy-5-fluorouridine (5'-DFUR) are 5-fluorouracil (5-FU) derivatives developed as anti-tumor pharmaceuticals. To evaluate immunotoxicities of these compounds, BDF1 mice were administered vehicle, 300-2700 mg (0.68-6.14 mmol)/kg/day of Ro 09-1390, or 100-900 mg (0.41-3.66 mmol)/kg/day of 5'-DFUR for 1 to 7 days, and effects on cellularity in lymphoid organs were assessed by immunohistochemistry as well as general toxicologic parameters. To distinguish compound-specific direct action from nonspecific indirect action caused by dietary reduction, dietary restriction groups were also included as control groups. Final body weight, thymus weight, bone marrow cell number (BMC), and leukocyte number were reduced with high dose of both compounds. Reduction of BMC in groups administered with Ro 09-1390 or 5'-DFUR was more severe than in dietary restriction groups given comparative amount of diet with compound-administered groups. Diffuse thymic cortical hypoplasia was observed in the highest dose of both compounds and more apparent in the Ro 09-1390 than in the 5'-DFUR. Focal nodular thymocyte hyperplasia was observed especially in the lower dose of 5'-DFUR. The results indicate that immunotoxic profiles of Ro 09-1390 and 5'-DFUR are very similar and characterized primarily by myelotoxicity and Ro 09-1390 is approximately two-times less toxic than 5'-DFUR on a molar basis in BDF1 mice.