Poster Presenter

Metabolism And Effect Of Telmisartan On Rat Hepatocytes In Primary Culture
Zuzana Cervinkova, Marcel Bima, Otto Kucera, Vilma Habrdova, Viktor Vorisek
Czech Republic

Sartans - highly selective non-peptide angiotensin II AT1 receptor antagonists were developed as potent drugs for treatment of hypertension. Sartans are metabolized in the liver by enzymatic oxidation and/or glucuronidation. Some of the oxidative and glucuronide metabolites of sartans have higher potency and longer half-life than the parent molecule. The aim of our work was to study potential toxic effect and metabolism of telmisartan on rat hepatocytes in vitro.

Hepatocytes were isolated from the liver of male Wistar rats (180 - 230 g) by two-step collagenase perfusion. Cells were resuspended in William´s E medium and plated on collagen-coated Petri dishes (density of 2 x 106 cells per dish). After attachment of hepatocytes the medium was removed and fresh media with telmisartan (TEL, Sigma Aldrich) in concentrations from 10 to 100 000 ng/ml were added. Toxicity of telmisartan was assessed at various time intervals up to 24 hours by lactatedehydrogenase (LDH) activity (Lachema) in culture medium and by activity of mitochondrial dehydrogenases (WST-1, Roche). HPLC-electrospray ionisation MS/MS method in positive ion mode with collision-induced dissociation was used for identification of parent molecule and major metabolite (1-O-glucuronide) in culture media and cells lyophilizates.

Telmisartan did not influence LDH activity in media even after 24 h of incubation, nevertheless activity of dehydrogenases was significantly decreased in all intervals in hepatocytes exposed to the highest doses of TEL (40 000 and 100 000 ng/ml; p<0.001). Metabolism of telmisartan was significantly impaired in hepatocyte cultures exposed to high doses of TEL (10 000 and 40 000 ng/ml; p<0.001).

This work was supported by grants: MSM 0021620820 and MSM 0021620817.