title: Effect of toremifene on antipyrine elimination in the isolated perfused rat liver.
abstract: Toremifene is a triphenylethylene antioestrogen with significant antitumor activity. It is structurally very similar to tamoxifen. Both drugs undergo extensive hepatic metabolism, and tamoxifen is known to inhibit hepatic mixed-function oxidases (MFO). Using the isolated perfused rat-liver model, we investigated the effect of toremifene on the elimination of antipyrine, a standard marker of MFO activity. Perfusate consisted of 20% red cells in a modified Krebs-Henseleit buffer, and 80 ml was recirculated at 14 ml/min for 3 h. High but clinically relevant steady-state toremifene levels of 3 and 10 micrograms/ml were achieved using bolus plus constant infusion into the reservoir. Elimination of 2.5 mg antipyrine was not inhibited by steady-state toremifene, but methanol (maximal perfusate concentration, 1.29%), the vehicle used for toremifene administration, caused a statistically significant increase in the antipyrine elimination half-life (mean, 1.4 +/- 0.2 h for controls vs 2.2 +/- 0.3 h for methanol; P < 0.05, n = 4). Whereas the methanol had no apparent effect on liver viability as assessed by bile flow and perfusate back-pressure, toremifene at a steady-state concentration of 10 micrograms/ml caused a statistically significant decrease in bile flow (value at 180 min, 0.22 +/- 0.05 ml/h as compared with 0.52 +/- 0.06 ml/h in the methanol control; P < 0.05) and a statistically significant increase in perfusate back-pressure (value at 180 min, 17.5 +/- 1.8 cm vs 11.0 +/- 2.6 cm in the methanol control; P < 0.05). Therefore, toremifene used at high doses can impair liver function in the isolated perfused rat liver, but it does not have any effect on antipyrine elimination.
authors.affiliation: Experimental Chemotherapy and Pharmacology Unit, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
authors.forename: L K
authors.initials: LK
authors.lastname: Webster
authors.forename: A G
authors.initials: AG
authors.lastname: Ellis
authors.forename: J F
authors.initials: JF
authors.lastname: Bishop
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D000432:Methanol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D017312:Toremifene / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D017312:Toremifene; D000983:Antipyrine; D000432:Methanol