Pharmacokinetics of 5-fluorouracil in mutant Nagase analbuminemic rats: faster metabolism of 5-fluorouracil via CYP1A.
It has been reported that plasma albumin concentrations were significantly lower in cancer patients than those in the healthy volunteers, and the expression and mRNA level of hepatic microsomal cytochrome P450 (CYP) 1A2 increased in mutant Nagase analbuminemic rats (NARs). After intravenous administration of 5-fluorouracil at a dose of 30 mg/kg to NARs, the time-averaged nonrenal clearance (Clnr) of the drug was significantly faster than the controls (51.3 versus 28.8 ml/min/kg), possibly due to an increase in the expression and mRNA level of CYP1A2 in NARs. In order to determine whether 5-fluorouracil is metabolized via CYP1A2 in male Sprague-Dawley rats, the rats were pretreated with 3-methylcholanthrene (a main inducer of CYP1A1/2 in rats). The Clnr of 5-fluorouracil was significantly faster (34.3 versus 27.3 ml/min/kg) in rats pretreated with 3-methylcholanthrene. The aforementioned data indicate that CYP1A is involved in the metabolism of 5-fluorouracil in rats.
Choi
Young H
YH
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
Bae
Soo K
SK
Kim
Sun O
SO
Lee
Myung G
MG
D000118:Acetylglucosaminidase / Q000235:genetics*; D000818:Animals; D000963:Antimetabolites / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D017551:Microdialysis; D011335:Proadifen / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000172:deficiency*
D000963:Antimetabolites; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D012709:Serum Albumin; D008748:Methylcholanthrene; D011335:Proadifen; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D000118:Acetylglucosaminidase; D005472:Fluorouracil