Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4′-hydroxylation status

Abstract

We studied the kinetic disposition and metabolism of E3810 [(+/-)-sodium 2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl ]-1H- benzimidazole], a new proton pump inhibitor, and omeprazole in 15 Japanese male volunteers, six of whom were poor metabolizers and nine of whom were extensive metabolizers of S-mephenytoin. All received once-daily 20 mg doses of E3810 or omeprazole for 7 days in a randomized crossover manner, with a 3-week washout period between the two trial phases. The parent drugs and their principal metabolites in plasma and urine were measured on days 1 and 7 after drug administration. The mean values for area under the plasma concentration-time curve (AUC) of omeprazole were 6.3- and 4.4-fold greater, whereas those of E3810 were 1.8- and 1.9-fold greater in poor metabolizers than in extensive metabolizers after the first and final doses, respectively. Although the mean AUC values for both drugs were significantly (p < 0.01 or p < 0.05) greater in poor metabolizers than in extensive metabolizers, the difference in the AUC between the two groups was smaller after E3810 than after omeprazole administration. The AUC of omeprazole tended to increase with the repeated doses in extensive metabolizers, whereas no such change was observed for E3810. The urinary excretions of the principal metabolite(s) of two proton pump inhibitors also reflected the data derived from plasma samples in relation to S-mephenytoin 4'-hydroxylation status. We conclude that the metabolism of two proton pump inhibitors is under coregulatory control of S-mephenytoin 4'-hydroxylase (CYP2C19), but that the magnitude of CYP2C19-mediated metabolism appears to differ between the two drugs. In contrast to omeprazole, the metabolism of E3810 is less saturable in extensive metabolizers during the repetitive dosings.

Proton Pump Inhibitors Inhibit Methotrexate Transport by Renal Basolateral Organic Anion Transporter hOAT3

“…Indeed, PPIs are mainly metabolized by CYP2C19, and because the impact of CYP2C19 polymorphism on drug concentrations has been well established, different concentrations should be considered (Goldstein, 2001;Simon et al, 2011). A previous group described the maximum concentration of carriers of a loss of function allele in the plasma for omeprazole (3.1 mM), lansoprazole (4.9 mM), and pantoprazole (11.5 mM) according to the CYP2C19 "poor metabolizer" phenotype (Regardh et al, 1990;Pue et al, 1993;Yasuda et al, 1995;Ieiri et al, 2001;Freston et al, 2003). The plasma concentrations were lower in carriers of the normal allele with an "extensive metabolizer" phenotype, 1.6, 2.4, and 5.4 mM for omeprazole, lansoprazole, and pantoprazole, respectively.…”

Enantioselective Disposition of Lansoprazole and Rabeprazole in Human Plasma

“…1). [9][10][11][12] Therefore, CYP2C19 contributes less to the overall metabolism of rabeprazole compared to lansoprazole, and is less in‰uenced by CYP2C19 genetic polymorphisms. 13) Genotypes of CYP2C19 are classied into three groups: homozygous extensive metabolizers (homEMs), heterozygous extensive metabolizers (hetEMs), and poor metabolizers (PMs).…”

Comparison of efficacies of dual therapy and triple therapy using rabeprazole in second‐line eradication of Helicobacter pylori in Japan

“…With regard to RPZ, a feature of this compound is that its action is much less influenced than other PPIs by different genotypes of CYP2C19, an isoenzyme of cytochrome P450 involved in the intrahepatic metabolism of PPIs. [22][23][24] A number of studies have examined …”