Biol. Pharm. Bull. 30(12) 2238—2243 (2007)

causes of emergency hospital admission in Japan, and it possibly results in life-threatening massive hemorrhage. Endoscopic clipping of the bleeding vessel is usually effective for treating gastrointestinal hemorrhage, but rebleeding occurs in 15 to 20% of patients. Higher intragastric pH promotes platelet aggregation, and the inhibition of gastric acid secretion to maintain neutral pH may stabilize clots and prevent recurrent bleeding. Intravenous administration of histamine H2-receptor antagonists has been widely used for the management of gastrointestinal hemorrhage, particularly after endoscopic clipping. However, gastric acid secretion is not solely regulated by the histamine H2-receptor, and tolerance to the antisecretory activity of H2-receptor antagonists frequently develops during infusion over 72-h periods, leading to a loss of pH control. Meta-analyses have also suggested that H2-receptor antagonists only have a weak beneficial effect. On the other hand, proton-pump inhibitors (PPIs) suppress gastric acid secretion by specific inhibition of the H /K ATPase enzyme system located on the secretory surface of gastric parietal cells. High doses of PPIs maintain the intragastric pH at a nearly neutral level, and inhibit acid production more effectively than an infusion of H2-receptor antagonists. Therefore, high-dose intravenous PPI therapy is theoretically superior to intravenous H2-receptor antagonist therapy for the prevention of recurrent bleeding. In fact, several studies have indicated that intravenous administration of PPIs is effective for the treatment of patients with gastrointestinal bleeding. It has been reported that PPIs (omeprazole and lansoprazole) are mainly metabolized by cytochrome P450 (CYP) 2C19. The genetic polymorphisms of CYP2C19 have been observed in Asian populations, and three polymorphic alleles, CYP2C19*1 (wild-type), CYP2C19*2, and CYP2C19*3, have been identified among Japanese. CYP2C19*2 causes a splicing defect in exon 5, and CYP2C19*3 creates a premature stop codon in exon 4. Therefore, these mutations lead to the complete loss of the enzymatic activity of CYP2C19. The allele frequencies of CYP2C19*2 and CYP2C19*3 among Japanese are reported to be 28.7% and 13.2%, respectively. It has been reported that genetic polymorphisms of CYP2C19 are responsible for the large interindividual variability in the pharmacokinetics of orally administered PPIs in Japanese populations. Recently, a new preparation for intravenous injection of lansoprazole was developed in Japan. In the present study, we evaluated the population pharmacokinetics of intravenously administered lansoprazole in healthy Japanese subjects using a nonlinear mixed effects model (NONMEM) program. We also evaluated the effect of CYP2C19 polymorphisms on proton pump inhibition by intravenously administered lansoprazole.