title: Chronic treatment with losartan results in sufficient serum levels of the metabolite EXP3179 for PPARgamma activation.
abstract: The losartan metabolite EXP3174 exhibits angiotensin II receptor 1 (AT1R)-blocking properties, whereas the metabolite EXP3179 potently induces the activity of the insulin-sensitizing peroxisome proliferator-activated receptor gamma (PPARgamma) as a partial agonist in vitro. We investigated whether chronic treatment with losartan leads to sufficient serum levels of EXP3179 to activate PPARgamma in monocytes derived from losartan-treated patients. Hypertensive patients (n=15) treated with losartan (100 mg/daily for at least the past 2 months) and untreated control patients (n=7) were included. Monocytes were extracted by negative isolation using a Dynal Monocyte Kit, followed by analysis of PPARgamma target gene expression (CD36, ABC transporter G1 [ABCG1]) by quantitative real-time RT-PCR. Serum was prepared before, 2, 4, and 6 hours after losartan (100 mg) ingestion for HPLC-based determination of losartan, EXP3174, and EXP3179. Chronic treatment with losartan resulted in basal levels of losartan, EXP3174, and EXP3179 of 348.3+/-101.8 ng/mL, 115.3+/-56.1 ng/mL, and 176.2+/-143.4 ng/mL, respectively. Levels of both EXP3174 and EXP3179 were time-dependently increased in serum with a maximum 2 hours after drug intake (1706.0+/-760.1 ng/mL, 808.9+/-618.2 ng/mL, respectively). In consonance with detectable PPARgamma-activating EXP3179 serum levels, monocytic PPARgamma target gene expression was significantly upregulated in patients treated with losartan by 3.75+/-0.95- and 252.02+/-46.86-fold for CD36 and ABCG1 (P=0.043, P=0.0045 versus control patients, respectively). This is the first clinical description of monocytic PPARgamma-target gene regulation by chronic treatment with losartan, which likely is mediated by its metabolite EXP3179. Our data show that sufficient serum levels of EXP3179 are present under losartan treatment. PPARgamma activation by AT1R-blockers may translate into synergistic beneficial actions in monocytes.
authors.affiliation: Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Hessische Strasse 3-4, Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
authors.forename: Oleg
authors.initials: O
authors.lastname: Tsuprykov
authors.forename: Jan
authors.initials: J
authors.lastname: Kaufmann
authors.forename: Jan
authors.initials: J
authors.lastname: Fritzsche
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
authors.forename: Matthias
authors.initials: M
authors.lastname: Goebel
authors.forename: Ilse Nirmala
authors.initials: IN
authors.lastname: Bähr
authors.forename: Paul-Laszlo
authors.initials: PL
authors.lastname: Hässle
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
authors.forename: Eckart
authors.initials: E
authors.lastname: Fleck
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Philipp
authors.initials: P
authors.lastname: Stawowy
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
mesh_terms: D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002465:Cell Movement; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D000077405:Irbesartan; D019808:Losartan / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D000077333:Telmisartan; D013777:Tetrazoles / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D007093:Imidazoles; D047495:PPAR gamma; D013777:Tetrazoles; C073600:2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-1H-imidazole-5-carboxaldehyde; C066026:losartan carboxylic acid; D000077405:Irbesartan; D019808:Losartan; D000077333:Telmisartan