title: Induction of hepatic drug-metabolising enzymes and tamoxifen metabolite profile in relation to administration route during low-dose treatment in nude rats.
abstract: Tamoxifen is the most used anticancer drug and is approved for chemoprevention. Little is known about the enzyme inducing properties of low-dose regimens and the influence of route of administration. In this study, nude rats received 5 mg/kg/day of tamoxifen orally or a 50 mg continuous-release pellet subcutaneously. The mRNAs for cytochrome P450-enzymes (CYPs), flavin-containing monooxygenase 1 (FMO1) and phase II drug-metabolising enzymes were quantified by real-time RT-PCR. Tamoxifen and metabolite concentrations were measured using HPLC. We observed a significant increase in CYP3A18 and FMO1 mRNA expression levels in the orally treated animals, whereas the increase in CYP3A2 expression did not reach statistical significance (p=0.057). No significant induction of enzyme expression was observed in rats that received subcutaneous (S.c.) treatment. After 33 days the serum levels of 4-hydroxytamoxifen (4OHtam), tamoxifen and N-desmethyltamoxifen (NDtam) in orally treated animals were 1.8+/-0.7, 11.1+/-3.2 and 11.4+/-3.8 ng/ml, respectively. In subcutaneously treated animals, tamoxifen and N-desmethyltamoxifen were detected in tissues, but not in serum. These data demonstrate that in contrast to the subcutaneous administration, low-dose oral tamoxifen induced tamoxifen-metabolising enzymes. Furthermore, the different routes of administration resulted in different serum and tissue levels of tamoxifen and metabolites.
authors.affiliation: Section for Endocrinology, Institute of Medicine, University of Bergen, Norway.
authors.forename: Elton Richard
authors.initials: ER
authors.lastname: Kisanga
authors.forename: Line L Haugan
authors.initials: LL
authors.lastname: Moi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gjerde
authors.forename: Gunnar
authors.initials: G
authors.lastname: Mellgren
authors.forename: Ernst A
authors.initials: EA
authors.lastname: Lien
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D007263:Infusions, Parenteral; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D010105:Oxygenases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D013629:Tamoxifen / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D016588:Anticarcinogenic Agents; D012333:RNA, Messenger; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D014453:Glucuronosyltransferase