Pharmacokinetic and Pharmacodynamic Properties of Lafutidine after Postprandial Oral Administration in Healthy Subjects: Comparison with Famotidine

Abstract

Lafutidine, 2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2-butenyl] acetamide, is a newly developed histamine H 2 -receptor antagonist. It is at present only approved in Japan as a tablet, and is used in the treatment of gastric ulcers, duodenal ulcers, and gastric mucosal lesions associated with acute gastritis and acute exacerbation of chronic gastritis.1) Lafutidine possesses a potent and longlasting gastric antisecretory effect mediated by H 2 -receptor blockade in animals.2) Lafutidine inhibits gastric acid secretion during the daytime (i.e., postprandial) as well as nighttime in clinical studies.3,4) However, its pharmacodynamics, the relationship between the plasma concentration and the drug response, such as intragastric pH, have not been reported. We believe it is clinically important to examine differences between lafutidine and famotidine to clarify the positioning of lafutidine in H 2 -receptor antagonists, because famotidine is the most commonly used H 2 -receptor antagonist in Japan. Thus, we compared the pharmacokinetic and pharmacodynamic properties of lafutidine and famotidine following postprandial oral administration in healthy subjects. MATERIALS AND METHODS SubjectsFive healthy Japanese male volunteers participated in this study. The subjects, aged 23-32 years and weighed 52-75 kg, had no history of gastrointestinal or hepatobiliary disease, and took no regular medications. Written informed consent was obtained from all subjects when they were enrolled in the study, which was approved by the Ethics Committee of Hiroshima University Hospital and conducted in compliance with the Declaration of Helsinki.Study Schedule This was a three-way (lafutidine, famotidine, and control) crossover study. At 11:00, a pH electrode was inserted through the nose, and its tip was positioned in the upper part of the gastric body, and from 11:30 to 17:00, the intragastric pH was measured. The pH electrode was connected to a portable digital recorder (PH-101Z; Chemical Instrument Co., Ltd., Tokyo, Japan), and the recordings were transferred to a personal computer for processing and analyzed using a software program. The median intragastric pH values per 30 min were calculated as the parameter representing the degrees of gastric acid suppression.Between 12:00 and 12:20, a standardized meal was eaten (650 kcal; protein 25 g, lipids 20 g, carbohydrate 80 g). At 12:30, lafutidine 10 mg (Stogar tablet 10 mg; UCB Japan Co., Ltd., Tokyo, Japan), famotidine 20 mg (Gaster tablet 20 mg; Astellas Pharma Inc., Tokyo, Japan), or water only (control) was orally administered. Venous blood samples were taken before and at 1, 1.5, 2, 2.5, and 4 h after drug administration.Assays of Lafutidine and Famotidine Plasma concentrations of lafutidine and famotidine were determined by HPLC according to the method of Itoh et al. 5) and Dowling et al.,6) respectively. Pharmacokinetic and Pharmacodynamic ModelingModel analysis was performed as shown in Fig. 1 Minami-ku, Hiroshima 734-8551, Japan. Received October 17, ...

A single LC–tandem mass spectrometry method for the simultaneous determination of four H2 antagonists in human plasma

“…A number of analytical methods have been reported for the determination of individual H 2 antagonists in human plasma since 1990 years, cimetidine [1][2][3][4][5][6][7][8], ranitidine [9][10][11][12][13][14][15][16][17], famotidine [18][19][20][21][22][23][24][25], and lafutidine [26][27][28][29]. Apart from some uncommonly used methods such as free capillary zone electrophoresis [4], micellar electrokinetic capillary chromatography [7], HPTLC [13], most reports utilized HPLC-UV method [1][2][3][4][5][6][7][9][10][11][12][13][14][15][16][18][19]…”

“…Apart from some uncommonly used methods such as free capillary zone electrophoresis [4], micellar electrokinetic capillary chromatography [7], HPTLC [13], most reports utilized HPLC-UV method [1][2][3][4][5][6][7][9][10][11][12][13][14][15][16][18][19][20][21][22][23]26,27]. Although HPLC method is mature and relatively economical, limitations such as sensitivity, selectivity and throughput were often encountered during the method development.…”

An open-label, randomized, cross-over bioequivalence study of lafutidine 10 mg under fasting condition

“…Many published comparative clinical studies have established the superiority of lafutidine over proton pump inhibitors [2,6,16] and other H2-receptor antagonists [1,25] . The normal dose of lafutidine is 10 mg once a day for gastric mucosal lesions associated with acute gastritis and acute exacerbation of chronic gastritis; 10 mg once a day as a preanesthetic medication; and 10 mg twice a day for gastric ulcers, duodenal ulcers and stomal ulcers [20] .…”

“…An internationally published pharmacokinetic study of lafutidine performed on healthy Japanese male volunteers showed a Cmax of 133.90 ng/mL and tmax of 1.84 h [1] . A similar study performed on healthy Chinese volunteers showed a Cmax of 151.55 ± 54.49 ng/mL and tmax of 1.60 ± 0.40 h [26] .…”

“…), is a newly developed second generation histamine H2-receptor antagonist [1] . It is absorbed in the small intestine, reaches gastric cells via the systemic circulation, and then directly and rapidly binds to gastric cell histamine H2 receptors, resulting in immediate inhibition of gastric acid secretion [2] .…”