Effects of PR-350, a newly developed radiosensitizer, on dihydropyrimidine dehydrogenase activity and 5-fluorouracil pharmacokinetics.
This study was designed to investigate the effects of PR-350, a newly developed radiosensitizer, on dihydropyrimidine dehydrogenase (DPD) activity and 5-fluorouracil (5-FU) pharmacokinetics in 8-week-old male Sprague-Dawley rats. In an in vitro study with hepatic cytosol, DPD activity was dose-dependently reduced by PR-350 at 0.5, 1.0, and 2.0 mmol/l to 75.5%, 64.9%, and 61.5%, respectively, of the control values. In an ex vivo study, DPD activities in hepatic cytosols obtained from animals which had received PR-350 over 4 days (200 mg/kg per day) were not significantly different from those in animals which had not. In an in vivo study, none of the pharmacokinetic parameters obtained from the plasma concentration-time profile of 5-FU were significantly altered by single i.v. injections of PR-350 (50, 100, or 200 mg/kg). However, (E)-5-(2)-(bromovinyl)uracil (BVU), a DPD inhibitor, significantly increased the half-life and area under the curve of 5-FU to 238.1% and 323.2%, respectively, of the control values. Administration of PR-350 over 4 days (200 mg/kg per day) did not affect either of these parameters. The administration of PR-350 significantly reduced the clearance (73.5% of control) and volume of distribution (71.0% of control) of 5-FU, but the alterations were much less than those caused by BVU. These results suggest that the effect of PR-350 on 5-FU pharmacokinetics is much less than that of BVU and that the enhancement of 5-FU toxicity by PR-350 is less than we initially anticipated.
Watanabe
M
M
Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki 216-8511, Japan.
Tateishi
T
T
Takezawa
N
N
Tanaka
M
M
Kumai
T
T
Nakaya
S
S
Kobayashi
S
S
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003600:Cytosol / Q000201:enzymology; D042943:Dihydrouracil Dehydrogenase (NADP); D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D010088:Oxidoreductases / Q000187:drug effects* / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000964:Antimetabolites, Antineoplastic; D007093:Imidazoles; D011838:Radiation-Sensitizing Agents; C106738:doranidazole; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil