ABSTRACT The effects of oral administration of clarithromycin (CLR), amoxicillin (AMX), and lansoprazole (LPZ) on gastric emptying in rats were investigated by a glass powder method and a phenol red method. By both test methods, no significant effects on gastric emptying were observed when CLR, AMX, or LPZ was administered alone or when the three drugs were administered concomitantly. The levels of gastrointestinal absorption of [ 14 C]CLR and [ 14 C]AMX were measured. Four hours after injection of [ 14 C]CLR or [ 14 C]AMX into the stomach and duodenum loops of rats, 86.63 and 1.27% of the original amount of [ 14 C]CLR administered were recovered in the contents of the stomach and duodenum loops, respectively, and 80.01 and 55.88% of the original amount of [ 14 C]AMX administered were recovered in the contents of the stomach and duodenum loops, respectively.

Triple therapy consisting of clarithromycin (CLR), lansoprazole (LPZ), and amoxicillin (AMZ) is effective as eradication therapy for patients with peptic ulcer disease and Helicobacter pylori infection. We evaluated the effects of LPZ and AMZ on the uptake of [C-14] CLR into the gastric tissue of rats. After administration of [C-14] CLR alone or in combination with LPZ and AMZ, the distributions of [C-14] CLR in the main organs and gastrointestinal tissues were compared. LPZ and AMZ had no effect on the distribution of [C-14] CLR in any tissue except gastric tissue. The concentration of radioactivity in gastric tissue was several times higher when [C-14] CLR was administered orally together with LPZ than when it was administered alone. The gastric emptying of [C-14] CLR became smaller in the case of the coadministration of LPZ. AMZ had no apparent influence on the disposition of [C-14] CLR. After the intravenous administration of [C-14] CLR, no effects of drug coadministration were evident. In vitro uptake of [C-14] CLR into gastric tissue was enhanced in the case of a high-pH environment. The uptake was not influenced by the concurrent presence of LPZ and AMZ. These results suggest that the penetration of [C-14]CLR possibly depends on elevated gastric pH, as gastric acid secretion was inhibited by LPZ, and this may be a primary factor in explaining why the concentration of [C-14] CLR at the target site, gastric tissue, was enhanced by the coadministration of LPZ.

The biotransformation of esonarimod (KE-298) [(+/-)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid], a new antirheumatic drug, was investigated in rats. Urinary and biliary excretions within 24 h after oral administration of 5 mg/kg [(14)C]esonarimod accounted for 89 and 10% of the dose, respectively. Initial metabolite analysis by liquid chromatography/electrospray ionization tandem mass spectrometry with negative ion mode, in which a mobile phase of 20 mM ammonium acetate (pH 4.6)/methanol with gradient-elution mode was used, failed to obtain any structural information on most of the metabolites due to poor sensitivity. To overcome this problem, postcolumn addition of 2-(2-methoxyethoxy)ethanol, a powerful signal-enhancing modifier, to the mobile phase was used, allowing pronounced signal enhancement and structural elucidation of urinary and biliary metabolites. The results of metabolite analysis suggested that esonarimod is predominantly biotransformed to a pharmacologically active metabolite, thiol-containing deacetyl-esonarimod (M-I), and subsequently undergoes extensive metabolism, mainly S-methylation followed by the combination of S-oxidation and oxidative conversion of the aromatic methyl group. No disulfide metabolites, such as M-I-cysteine mixed disulfide and M-I-dimer, were found in the excreta. This finding is probably evidence supporting the notion that the reactivity of the thiol moiety of M-I with macromolecules in vivo is extremely lower than that of common thiol-containing drugs.

ABSTRACT Triple therapy consisting of clarithromycin (CLR), lansoprazole (LPZ), and amoxicillin (AMZ) is effective as eradication therapy for patients with peptic ulcer disease and Helicobacter pylori infection. We evaluated the effects of LPZ and AMZ on the uptake of [ 14 C]CLR into the gastric tissue of rats. After administration of [ 14 C]CLR alone or in combination with LPZ and AMZ, the distributions of [ 14 C]CLR in the main organs and gastrointestinal tissues were compared. LPZ and AMZ had no effect on the distribution of [ 14 C]CLR in any tissue except gastric tissue. The concentration of radioactivity in gastric tissue was several times higher when [ 14 C]CLR was administered orally together with LPZ than when it was administered alone. The gastric emptying of [ 14 C]CLR became smaller in the case of the coadministration of LPZ. AMZ had no apparent influence on the disposition of [ 14 C]CLR. After the intravenous administration of [ 14 C]CLR, no effects of drug coadministration were evident. In vitro uptake of [ 14 C]CLR into gastric tissue was enhanced in the case of a high-pH environment. The uptake was not influenced by the concurrent presence of LPZ and AMZ. These results suggest that the penetration of [ 14 C]CLR possibly depends on elevated gastric pH, as gastric acid secretion was inhibited by LPZ, and this may be a primary factor in explaining why the concentration of [ 14 C]CLR at the target site, gastric tissue, was enhanced by the coadministration of LPZ.

To determine the in vivo uptake by the rat lung, each derivative was injected into the external jugular vein. Five seconds after the injection, the lung was removed and homogenized. The supernatant obtained by centrifugation of the homogenate at 3000 rpm (2,000×g) for 10 min was used for the microbiological assay. The assay was performed by the paper disc method, using Micrococcus luteus ATCC 9341 as the test organism