Uridine-induced hypothermia in mice and rats in relation to plasma and tissue levels of uridine and its metabolites.
Administration of high-dose uridine or cytidine (3500 mg/kg) resulted in severe hypothermia of 6-10 degrees C in mice. This effect of uridine was observed in three different mouse strains, C57B1/6, Balb/c, and Swiss. A high-dose of uridine also caused hypothermia in Wistar rats. Co-infusion of uridine with benzylacyclouridine, an inhibitor of uridine phosphorylase, partially prevented uridine-mediated hypothermia in mice. A low dose of uridine (100 mg/kg) resulted in a slight increase in temperature. Plasma pharmacokinetics of uridine (at 3500 mg/kg) were studied in two mouse strains, C57B1/6 and Balb/c, and those of cytidine only in C57B1/6 mice. Peak plasma concentrations of uridine in both strains after uridine administration were about 20 mM (at 30-60 min). The peak plasma concentration of cytidine in C57B1/6 mice after cytidine administration was about 12 mM and that of uridine, 1.3 mM. The mean residence time for uridine was about 105 min. The area under the plasma concentration-time curve for uridine was about 50 mmol h/l, and that for cytidine, about 25 mmol h/l. In various tissues of C57B1/6 mice the levels of uridine, uracil and total uracil and cytosine nucleotide pools were determined before and 2 h after uridine administration. Uridine levels increased about 53-fold in liver, about 70-fold in a colon tumor, and only about 7-fold in brain, while the corresponding uracil levels increased about 9-fold, 4-fold and 11-fold, respectively. Total uracil nucleotide pools increased about 8-fold, 3.2-fold and 1.6-fold, respectively. Cytosine nucleotide pools did not increase in the brain. In conclusion, high-dose uridine administration caused severe hypothermia. Plasma levels of uridine and uracil were enhanced to a considerably higher extent than the levels in the tissues. The hypothermia might be related to breakdown products of uridine, since inhibition of uridine breakdown partially prevented hypothermia and since in brain uracil nucleotide levels were only slightly increased after uridine administration, while those of uracil were more markedly increased than in other tissues.
Peters
G J
GJ
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
van Groeningen
C J
CJ
Laurensse
E J
EJ
Lankelma
J
J
Leyva
A
A
Pinedo
H M
HM
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D003562:Cytidine / Q000097:blood / Q000633:toxicity; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D007035:Hypothermia / Q000139:chemically induced*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051381:Rats; D011919:Rats, Inbred Strains; D013767:Tetrahydrouridine / Q000633:toxicity; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D014529:Uridine / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors
C034753:5-benzylacyclouridine; D013767:Tetrahydrouridine; C029221:1-(2'-deoxy-beta-D-glucopyranosyl)thymine; D014498:Uracil; D003562:Cytidine; D014543:Uridine Phosphorylase; D003564:Cytidine Deaminase; D013936:Thymidine; D014529:Uridine