title: Relationship between AUC of 5'-DFUR and toxicity of capecitabine, fluoropyrimidine carbamate analogs, and 5'-DFUR in monkeys, mice, and rats.
abstract: 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.
authors.affiliation: Pre-clinical Research Department, Research Division, Chugai Pharmaceutical Co. Ltd., Fuji Gotemba Research Labs, 1-135 Komakado, Gotemba-city, Shizuoka 412-8513, Japan. shindohdt@chugai-pharm.co.jp
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shindoh
authors.forename: Akira
authors.initials: A
authors.lastname: Kawashima
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shishido
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Nakano
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Ikuo
authors.initials: I
authors.lastname: Horii
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D019540:Area Under Curve; D000069287:Capecitabine; D002219:Carbamates / Q000633:toxicity; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000633:toxicity; D005467:Floxuridine / Q000493:pharmacokinetics* / Q000633:toxicity*; D005472:Fluorouracil / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000964:Antimetabolites, Antineoplastic; D002219:Carbamates; D005467:Floxuridine; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil; C025034:doxifluridine