Effect of clarithromycin on the enantioselective disposition of lansoprazole in relation to CYP2C19 genotypes

The aim of this study was to examine the effect of clarithromycin, a CYP3A4 inhibitor, on the enantioselective disposition of lansoprazole among three different CYP2C19 genotype groups in healthy Japanese subjects. These subjects included 6 each of homozygous extensive metabolizers (homEMs), heterozygous extensive metabolizers (hetEMs), and poor metabolizers (PMs). In the EMs of CYP2C19, clarithromycin markedly increased C max and the AUC 0–∞ of ( S )‐lansoprazole and ( S )‐hydroxylansoprazole compared with those of the corresponding ( R )‐enantiomers. Clarithromycin significantly increased C max and the AUC 0–∞ of ( S )‐lansoprazole in the homEMs by 110% and 115%, respectively, and in the hetEMs by 105% and 103%, respectively, compared with placebo. Furthermore, clarithromycin slightly prolonged the elimination half‐life of ( R )‐lansoprazole in the homEMs and hetEMs but did not alter that of ( S )‐lansoprazole. In the of PMs CYP2C19, clarithromycin significantly increased C max and the AUC 0–∞ and significantly prolonged the elimination half‐lives of ( R )‐ and ( S )‐lansoprazole by 51% and 49%, respectively. The present study suggests that there are significant drug interactions between ( R )‐ or ( S )‐lansoprazole and clarithromycin in EMs by inhibiting the CYP3A4‐catalyzed sulfoxidation primarily during the first pass, whereas in PMs, the overall metabolism of lansoprazole is inhibited. Chirality 17:338–344, 2005. © 2005 Wiley‐Liss, Inc.