Rate-limiting biotransformation of triamterene is mediated by CYP1A2
Fuhr, U.; Kober, S.; Zaigler, M.; Mutschler, E.; Spahn-Langguth, H.
International Journal of Clinical Pharmacology and Therapeutics 43(7): 327-334
2005
ISSN/ISBN: 0946-1965 PMID: 16035375 Document Number: 587276
Objective: Triamterene (TA), a potassium-sparing diuretic, is extensively metabolized by hydroxylation in 4'-position and subsequent conjugation by cytosolic sulfotransferases. To identify the cytochrome P450 enzyme(s) catalyzing hydroxylation of triamterene (the rate-limiting step in the formation of the sulfate ester (STA)), in vitro incubation studies were performed with human liver microsomes. Methods: Initial rates of TA hydroxylation (0 - 300 mu M) were determined during a ten-minute-incubation period with liver microsomes of two donors. The role of individual CYP enzymes was determined by pre-incubation with selective inhibitors/alternative substrates. Vice versa, the effect of TA (0 - 500 mu M) on 3-demethylation of caffeine (0 - 1,000 mu M) was assessed. Metabolite concentrations were estimated by reversed-phase HPLC methods. Results: TA K-m values without inhibitors were 60 and 142 mu M, V-max was 177 and 220 pmol/min/mg-protein, respectively. Mean inhibitor induced changes of 4'-hydroxy-TA formation were as follows: Furafylline 25 mu M (CYP1A2), complete inhibition (-100%); omeprazole 250 mu M (CYP1A2 inhibitor/CYP2C19 substrate), -30%; coumarin 25 mu M (CYP2A6), -11%; quinidine 25 mu M (CYP2D6),-9%; ketoconazole 25 mu M (CYP3A), -18%; and erythromycin 250 mu M (CYP3A), -8%. In the reverse inhibition studies, TA competitively inhibited caffeine 3-demethylation with K-i values of 65 and 111 mu M, respectively. Conclusion: 4'-hydroxylation of TA in humans appears to be mediated exclusively by CYP1A2. Inhibition or induction of CYP1A2 will change the time course of both TA and its active phase-II metabolite. The net pharmacodynamic effect of such changes is difficult to predict and needs to be evaluated in clinical studies.