Oxidation of the antihistaminic drug terfenadine in human liver microsomes. Role of cytochrome P-450 3A(4) in N-dealkylation and C-hydroxylation.

The antihistaminic drug terfenadine, alpha-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1- piperidinebutanol (Seldane), is of interest because of its lack of sedative properties. Major routes of metabolism include oxidative N-dealkylation to 4-(hydroxydiphenylmethyl)-piperidine (1) and oxidation of a tert-butyl methyl group to a primary alcohol (2), which is subsequently oxidized to a carboxylic acid. Rates of formation of 1 and 2 varied approximately 30-fold in the 17 human liver microsomal samples examined and were highly correlated with each other, suggesting that the same enzyme may be involved in both oxidations. The rates of formation of 1 and 2 were both correlated with rates of nifedipine oxidation (a marker of cytochrome P-450 (P-450) 3A4) but not with markers for other human P-450s. Microsomal oxidation of (both enantiomers of) terfenadine to 1 and 2 was markedly inhibited by gestodene, a selective mechanism-based inactivator of P-450 3A enzymes but not by any of several other P-450 inhibitors. Antibodies raised against P-450 3A4 could inhibit most of the oxidation of (both enantiomers of) terfenadine to 1 and 2 in a microsomal sample having high catalytic activity but antibodies recognizing other P-450s had no effect. The oxidation of terfenadine to 1 and 2 was catalyzed by purified human liver microsomal P-450 3A4 and by partially purified yeast recombinant P-450 3A4. These results provide evidence that P-450 3A4 (and possibly other P-450 3A enzymes) play a major role in the oxidation of (both enantiomers of) terfenadine to both of its major oxidation products.(ABSTRACT TRUNCATED AT 250 WORDS)