Lansoprazole 5-hydroxylation

The experimental conditions for examining the in vitro metabolism of the drug candidate by a bank of human liver microsomes are based on the results of experiments described in Steps 2 and 3 (i.e., experiments designed to establish initial rate conditions and Km and Vmax). In order to obtain clinically relevant results, the metabolism of the drug candidate by human liver microsomes must be examined at pharmacologically relevant concentrations of the drug candidate, as illustrated for lansoprazole 5-hydroxylation in Figure 20. 

Sohn DR, Kwon JT, Kim HK, et al. Metabolic disposition of lansoprazole in relation to the S-mephenytoin 4 -hydroxylation phenotype status. Clin Pharmacol Ther 1997 61 574-582. 

Omeprazole is rapidly and completely metabolized after intestinal absorption. Oxidative processes for metabolism are predominant and three main metabolites of omeprazole have been identified the corresponding sulphone and sulphide as well as hydroxyomeprazole. Omeprazole sulphone is further metabolized or it is eliminated in the faeces. Renal excretion is the predominant route of elimination of omeprazole metabolites [20, 28, 110]. The metabolism of lansoprazole in humans is comparable to that of omeprazole it is converted to hydroxylansoprazole, lansoprazole-sulphone, lansoprazole-sulphide and the hydroxylated sulphone [111]. 

In a randomised, crossover study 21 subjects were given a single 60-mg dose of lansoprazole with either 200 mL of water or freshly-squeezed grapefruit juice. The AUC of lansoprazole was slightly increased by 18%, and the formation of the sulphone metabolite was reduced by the grapefruit juice. Metabolism to the hydroxyl metabolite was not significantly affected. ... 

The AUC of a single 60-mg dose of lansoprazole was raised 1.55-fold to 1.8-fold by clarithromycin 500 mg twice daily for 6 days in both extensive and poor metabolisers of CYP2C19. In another study in healthy subjects, the AUC of lansoprazole 30 mg twice daily was increased by just 25% by clarithromycin 500 mg twice daily and amoxicillin 1 g twice daily for 4 days. The AUC of the hydroxyl metabolite of clarithromycin was also increased by about 25%. ... 

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