Gastrointestinal absorption of a new reversible proton pump inhibitor, YJA-20379-8, and its pharmacokinetics after oral administration in acetic acid-induced gastric ulcer in rats.

The absorption of YJA-20379-8 (3-butyryl-4-[5-(R)-(+)-methylbenzylamino]-8-ethoxy-1,7-naphthyrid ine) from various rat gastrointestinal segments was evaluated using in-situ closed-loops. The pharmacokinetics of the drug were also evaluated after oral administration to rats with acetic acid-induced gastric ulcer (AIURs). The concentrations of YJA-20379-8 in the biological samples were analyzed by HPLC. The absorption of YJA-20379-8 from stomach and jejunum was fast, but approximately 50% of the drug was recovered from each segment at 24 h. The total areas under the plasma concentration-time curves from time zero to 24h (AUC(0-24h)) were 161, 392, 233, 365, and 226 microg min mL(-1) for stomach, duodenum, jejunum, ileum, and colon, respectively. After oral administration of the drug, the plasma concentrations and the resultant AUC (0- 12h) were not significantly different between control and AIURs. The detection limits of YJA-20379-8 in human plasma and urine were 50 and 100 ng mL(-1), respectively. The results suggest that modification of the oral dose of YJA-20379-8 may not be required in gastric ulcer patients if the present rat pharmacokinetic data could be extrapolated to man.     

Pharmacokinetics of a new proton pump inhibitor, YJA-20379-8, after intravenous and oral administration to spontaneously hypertensive rats and DOCA-salt-induced hypertensive rats

The purpose of this study was to investigate the causes for the differences observed in the pharmacokinetics of YJA-20379-8 in 16-week-old spontaneously hypertensive rats (SHRs). To see if the hereditary characteristics of SHRs was the cause, 20 mg/kg of the drug was intravenously infused over 15 min and 50 mg/kg of the drug was orally administered to 6-week-old SHRs and 16-week-old SHRs and their age-matched control Kyoto-Wistar (KW) rats. Also to see if the hypertensive status itself was the cause, the same doses were administered to 16-week-old deoxycorticosterone acetate (DOCA) salt-induced hypertensive rats (DOCA-salt rats) and their age-matched control Sprague-Dawley rats. The areas under the plasma concentration-time curve from time zero to time infinity (for intravenous study) and to the last sampling time in plasma (for oral study) were significantly smaller after both intravenous and oral administration, and the total body clearances of the drug were significantly faster after intravenous administration to 6-week-old SHRs, 16-week-old SHRs, and 16-week-old DOCA-salt rats than those in their respective age-matched control rats. The above pharmacokinetic parameter changes in 16-week-old SHRs were due to both hereditary characteristic of SHRs and the hypertensive status itself.     

Pharmacokinetics of a new proton-pump inhibitor, YJA-20379-8, after intravenous and oral administration to rats with streptozotocin-induced diabetes mellitus.

Because physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics of the drugs used to treat the disease, the pharmacokinetics of a new proton pump inhibitor, YJA-20379-8, were investigated after intravenous and oral administration of the drug (50 mg kg(-1)) to control rats and to rats with streptozotocin-induced diabetes mellitus (SIDM). After intravenous administration of YJA-20379-8 to SIDM rats, plasma concentrations of the drug were significantly higher and this resulted in a significantly greater AUC (area under the concentration-time curve; 2520 +/- 366 compared with 1870+/-272 microg min mL(-1)). This was because of significantly slower clearance (CL; 19.5+/-2.88 compared with 27.2+/-3.93 mL min(-1) kg(-1)) in SIDM rats. The significantly slower metabolism of YJA-20379-8 in SIDM rats was confirmed by an in-vitro tissue metabolism study; the amounts of YJA-20379-8 remaining in the liver (27.1+/-5.19 compared with 18.9+/-8.24 microg(g tissue)(-1)) were significantly greater after 30-min incubation of the drug (50 microg) with supernatant fractions obtained from the tissues by centrifugation at 9000 g. After oral administration of YJA-20379-8 to SIDM rats the plasma concentrations of the drug were significantly lower and this resulted in significantly smaller AUC (128+/-31.0 compared with 219+/-45.6 microg min mL(-1)). This was because of reduced gastrointestinal absorption of YJA-20379-8 in SIDM rats; the amounts of the oral dose recovered as unchanged drug from the entire gastrointestinal tract after 24h were significantly greater (32.9 compared with 19.2%) in SIDM rats. The tissue distribution of YJA-20379-8 was not affected by SIDM.     

Dose-dependent pharmacokinetics of a new reversible proton pump inhibitor, DBM-819, after intravenous and oral administration to rats: hepatic first-pass effect.

The dose-dependent pharmacokinetic parameters of DBM-819 were evaluated after intravenous (5, 10 and 20 mg/kg) and oral (10, 20 and 50 mg/kg) administrations of the drug to rats. The hepatic first-pass effect was also measured after intravenous and intraportal administrations of the drug, 10 mg/kg, to rats. After intravenous administration, the dose-normalized (based on 5 mg/kg) area under the plasma concentration-time curve from time zero to time infinity, AUC, at 20 mg/kg (27.0 and 45.8 microg min/ml) was significantly greater than that at 5 mg/kg due to saturable metabolism. After oral administration, the dose-normalized (based on 10 mg/kg) AUC(0-12 h) at 50 mg/kg (25.1, 18.3 and 49.2 microg min/ml) was significantly greater than those at 10 and 20 mg/kg again due to saturable metabolism. After oral administration of DBM-819, 10 mg/kg, 2.86% of oral dose was not absorbed and the extent of absolute oral bioavailability (F) was estimated to be 46.7%. After intraportal administration of DBM-819, 10 mg/kg, the AUC was 51.9% of intravenous administration, suggesting that approximately 48.1% was eliminated by liver (hepatic first-pass effect). The considerable hepatic first-pass effect of DBM-819 was also supported by significantly greater AUC of M3 (3.70 and 6.86 microg min/ml), a metabolite of DBM-819, after intraportal administration. The AUCs of DBM-819 were not significantly different (comparable) between intraportal and oral administrations of the drug, 10 mg/kg, suggesting that gastrointestinal first-pass effect of DBM-819 was almost negligible in rats. At 10 mg/kg oral dose of DBM-819, the hepatic first-pass effect was approximately 48.1%, F was approximately 46.7 and 2.86% was not absorbed from gastrointestinal tract in rats.     

Dose-independent pharmacokinetics of a new reversible proton pump inhibitor,KR-60436, after intravenous and oral administration to rats: gastrointestinal first-pass effect

Dose-independent pharmacokinetic parameters of KR-60436, a new proton pump inhibitor, were evaluated after intravenous (i.v.; 5, 10, and 20 mg/kg) and oral (20, 50, and 100 mg/kg) administration to rats. The hepatic, gastric, and intestinal first-pass effects were also measured after iv, intraportal (i.p.), intragastric (i.g.), and intraduodenal (id) administrations to rats of a dose of 20 mg/kg. The areas under the plasma concentration-time curve from time to zero to time infinity (AUCs) were independent of iv and oral dose ranges studied; the dose-normalized AUCs were 83.0-104 microg. min/mL (based on 5 mg/kg) and 78.4-96.8 microg. min/mL (based on 20 mg/kg) for iv and oral administration, respectively. After an oral administration at a dose of 20 mg/kg, approximately 3% of the oral dose was not absorbed, and the extent of absolute oral bioavaliability (F) was estimated to be 18.8%. The AUCs of KR-60436 after i.g. and i.d. administration at a dose of 20 mg/kg were significantly smaller (82.4 and 57.5% decrease, respectively) than that after an i.p. administration at a dose of 20 mg/kg, suggesting that gastrointestinal first-pass effect of KR-60436 was approximately 80% of oral dose in rats (the gastric first-pass effect was approximately 25%). After an i.p. administration at a dose of 20 mg/kg, the AUC was 77.6% of an iv administration, suggesting that hepatic first-pass effect was approximately 22% of KR-60436 absorbed into the portal vein. Note that the value of 22% was equivalent to approximately 4% of the oral dose. Because only 17% of oral dose was absorbed into the portal vein, the low F of KR-60436 in rats was mainly due to considerable gastrointestinal first-pass effect, which was approximately 80% (the gastric first-pass effect was approximately 25%) of oral dose.     

Pharmacokinetics of a new reversible proton pump inhibitor,YH1885, after intravenous and oral administrations to rats and dogs: hepatic first-pass effect in rats

The pharmacokinetics of YH1885 were evaluated after intravenous (iv) and oral administrations of the drug to rats and dogs. The reason for the low extent of bioavailability (F) of YH1885 after oral administration of the drug to rats and the absorption of the drug from various rat gastrointestinal (GI) segments were also investigated. After iv administration of YH1885, 5–20 mg kg⁻¹, to rats, the pharmacokinetic parameters of YH1885 seem to be independent of the drug at the dose ranges studied. After oral administration of YH1885, 50–200 mg kg⁻¹, to rats, the area under the plasma concentration–time curve from time zero to 12 or 24 h (AUC_{0–12 h} or AUC_{0–24 h}) was proportional to the oral dose of the drug, 50–100 mg kg⁻¹, however, the AUC_{0–24 h} value at 200 mg kg⁻¹ increased with less proportion to the dose increase (324, 689, and 815 μg · min mL⁻¹ for 50, 100, and 200 mg kg⁻¹, respectively) due to the poor water solubility of the drug. This was proved by the considerable increase in the percentages of the oral dose remaining in the entire GI tract as unchanged YH1885 at 24 h (11.8, 15.3, and 42.8% for 50, 100, and 200 mg kg⁻¹, respectively). The F value after oral administration of YH1885 to rats was relatively low; the value was approximately 40% at the oral dose of 50 and 100 mg kg⁻¹. The reason for the low F in rats was investigated. The liver showed the highest metabolic activity for YH1885 based on an in vitro rat tissue homogenate study; hence, the liver first-pass effect was estimated. The value of AUC after intraportal administration of the drug, 5 mg kg⁻¹, was approximately 70% (116 versus 163 μg · min mL⁻¹) of that after iv administration of the drug, 5 mg kg⁻¹, to rats; the liver first-pass effect of YH1885 in rats was estimated to be approximately 30%. The total body clearance of YH1885 after iv administration of the drug, 5–20 mg kg⁻¹, to rats were considerably lower than the cardiac output of rats, indicating that the lung and/or heart first-pass effect of YH1885 could be negligible in rats. After oral administration of YH1885, 50 and 100 mg kg⁻¹, to rats, the F value was approximately 40%, and approximately 15% of the oral dose was recovered from the entire GI tract as unchanged YH1885 at 24 h, and 30% of the oral dose disappeared with the liver first-pass effect. Therefore, the remainder, approximately 15% of the oral dose, could have disappeared with the small intestine first-pass effect and/or degradation of the drug in the GI tract. YH1885 was absorbed from ileum, duodenum, and jejunum of rat, however, YH1885 was under the detection limit in plasma when the drug was instilled into the rat stomach and large intestine. After iv administration of YH1885, 5–20 mg kg⁻¹, to dogs, the pharmacokinetic parameters of YH1885 also seemed to be independent of the drug at the dose ranges studied. However, after oral administration of YH1885, 0.5 and 2 g per whole body weight, to dogs, the AUC_{0–10 h} values were not significantly different (96.8 versus 98.2 μg · min mL⁻¹) and this could be due to the poor water-solubility of the drug. YH1885 was not detected in the urine after both iv and oral administration of the drug to both rats and dogs. Copyright © 1998 John Wiley & Sons, Ltd.     

Inhibitory action of YJA20379, a new proton pump inhibitor onHelicobacter pylori growth and urease

The activities of two types of antiulcer agents against 9 strains ofHelicobacter pylori (H. pylori) were determined by the agar dilution method. The antiulcer agents were YJA20379, a newly synthesized proton pump inhibitor developed by Yung-Jin Pharmaceutical company, and omeprazole. Both compounds were found to have significant activities against this organism. The MIC values of YJA20379 and omeprazole were 11.7 and 31.25 µg/ml, respectively. In addition, the inhibitory potency of both compounds was investigated onH. pylori urease which is believed to be an important colonization and virulence factor in the pathogenesis of gastritis and peptic ulcers. These compounds dose-dependently inhibited urease extracted with distilled water and their IC₅₀ values were 16.4×10^?5 M and 14.3×10^?5 M, respectively. In addition, a pH-dependent study to determine whether inhibitory potency would be activated by acid condition was performed. It was found that unlike omeprazole, YJA20379 was not affected by acid condition. To determine the inhibition pattern and optimal concentration of substrate, kinetics were evaluated at various pH levels (pH 5.0, 7.0, and 8.5). The data show that YJA20379 noncompetitively inhibitedH. pylori urease and K_M/K_i values were 0.96 mM/60 µM (pH 5.0), 0.56 mM/141.5 µM (pH 7.0), and 1.94 mM/34 µM (pH 8.5), respectively. Based on data obtained, it is concluded that YJA20379 is a significant inhibitor ofH. pylori growth and urease and therefore, taking these results into consideration, YJA20379 might be a beneficial therapy for gastritis and peptic ulcers induced byH. pylori.     

General pharmacological properties of YJA 20379-1, a novel proton pump inhibitor with antiulcer activities

The general pharmacological properties of YJA 20379-1 (2-amino-4,5-dihydro-8-phenylimidazo[2,1-b]thiazolo[4,5-g]benzo thi azole), a novel proton pump inhibitor with antiulcer activities, were investigated in mice, rats, guinea pig and rabbits. YJA 20379-1 at oral doses of 50, 100 and 200 mg/kg did not affect the general behaviour, hexobarbital hypnosis, motor coordination and body temperature in mice. The drug does not have analgesic and anticonvulsant action at 200 mg/kg p.o. The locomotor activity was not affected at 100 mg/kg p.o., but at 200 mg/kg, the activity was suppressed. YJA 20379-1 (at 2 x 10(-4) g/ml) did neither produce any contraction nor relaxation of isolated organs such as rat fundus, rat uterus, guinea pig ileum and guinea pig vas deferens, and the drug did not antagonize the contractile response to several spasmogens, such as histamine, acetylcholine, serotonin and oxytocin, and the drug up to 200 mg/kg p.o. did not affect pupil size of mice. The intestinal propulsion in mice was not affected up to 200 mg/kg p.o. The gastric emptying in rats was not affected at 100 mg/kg p.o., even if retardation in gastric emptying occurred at 200 mg/kg. YJA 20379-1 did not show anti-inflammatory action nor did it affect urinary excretion up to 200 mg/kg p.o. From these results, it is suggested that YJA 20379-1 at the high dose of 100 mg/kg p.o. may not exert any adverse effects.     

Gastrointestinal first-pass effect of furosemide in rats

The first-pass effect of furosemide was investigated in rats. Furosemide intravenous solution (20 mg kg(-1) Lasix), was administered via the jugular vein and the portal vein, orally, and instilled directly into the duodenum of rats. The first-pass effects of furosemide by lung, heart, and liver seemed to be negligible in rats. The absolute bioavailability of furosemide was 28.9 and 48.3% after oral and intraduodenal administration, respectively. Based on the gastrointestinal (GI) recovery study, 68.3 and 69.5% of furosemide were found to have disappeared mainly due to absorption and/or metabolism from rat GI tract after oral and intraduodenal administration, respectively. The results indicate that gastrointestinal and intestinal first-pass effects of furosemide were approximately 40% (68.3-28.9%) and 20% (69.5-48.3%) of the dose, respectively.     

General pharmacology of IY-81149, a new proton pump inhibitor

IY-81149 (2-[(4-methoxy-3-methyl)-2-pyridinyl]methylsulfinyl -5-(1H-pyrrol-1-yl)-1H-benzimidazole, CAS 172152-36-2) is a new proton pump inhibitor and expected to be an antiulcer drug. Its general pharmacological effects were studied in this paper. The doses given were vehicle control, 0.3, 1, 3, 100, 300 and 1000 mg/kg and were administered orally. The animals used in this study were mouse, rat, guinea pig and beagle dog. IY-81149 decreased spontaneous locomotor activity at 1000 mg/kg and showed a weak effect in motor performance at 300 and 1000 mg/kg. IY-81149 prolonged the hexobarbital-induced sleeping time dose dependently at 100, 300 and 1000 mg/kg. Oral administration of IY-81149 caused a dose-dependent hypothermic effect up to 300 mg/kg and showed analgesic effect at 1000 mg/kg. IY-81149 produced an antisecretory effect in pylorus ligated rats. The total gastric volume and acidity were significantly decreased at doses ranging from 1 to 3 mg/kg. However, IY-81149 had no effects on general behavior, did not show anticonvulsant activity, and did not affect blood pressure and heart rate, LVP (left ventricular peak systolic pressure), LVEDP (left ventricular end diastolic pressure), LVDP (left ventricular developing pressure), DP (double product), HR (heart rate), CFR (coronary flow rate), smooth muscle contraction, respiration, intestinal transport and renal function. These findings demonstrate that IY-81149 possesses weak central nervous system action and inhibitory effects on microsomal enzymes and gastric secretion after single administration. The results suggest that IY-81149 does not exert any notable pharmacological effects on the cardiovascular system, autonomic nerve system or smooth muscle function at all doses tested.     

General pharmacological properties of YJA20379-8, a new H+/K(+)-ATPase inhibitor with anti-ulcer activities

The general pharmacological properties of YJA20379-8 (3-butyryl-4-[(R)-1-methylbenzylamino]-8-ethoxy-1,7-naphthyridine, CAS 187654-40-6), a new H+/K(+)-ATPase inhibitor with anti-ulcer activities, were investigated in mice, rats and guinea pigs. YJA20379-8 at oral doses of 25, 50 and 100 mg/kg did not affect the locomotor activity, hexobarbital hypnosis and motor coordination in mice. The drug did not have analgesic action and anticonvulsant action at the doses of 100 mg/kg p.o. The respiration and blood pressure were not affected at 10 mg/kg i.v. in rats. YJA20379-8 at 2 x 10(-4) g/ml did neither produce any contraction nor relaxation of isolated organs, such as guinea pig ileum, rat fundus, rat uterus and guinea pig vas deferens, and the drug antagonized the contractile responses to several spasmogens, such as acetylcholine, histamine, serotonin, L-phenylephrine, oxytocin and BaCl2. The drug up to 100 mg/kg p.o. did not affect pupil size and the intestinal propulsion of mice. And it did not show an anticarrageenan action at 100 mg/kg. In this general pharmacology study, hypothermic effect in mice, retardation in gastric emptying in rats, decreases in urine excretion in rats at oral doses of 50 and 100 mg/kg of YJA20379-8 and the spasmolytic activity could be found. However, no other effects were exhibited at a high oral dose of 100 mg/kg in animals in this study.     

Biochemical and pharmacological properties of a new proton pump inhibitor, 2-amino-4,5-dihydropyrido[1,2-a]thiazolo [5,4-g] benzimidazole (YJA20379-5)

This study was designed to determine biochemical and pharmacological properties of a newly synthesized benzimidazole derivative, 2-amino-4,5-dihydropyrido [1,2-a] thiazolo [5,4-g] benzimidazole (YJA20379-5)in vitro andin vivo. In the leaky membrane vesicles of pig gastric mucosa, YJA20379-5 inhibited the K⁺-stimulated H⁺,K⁺-ATPase activity in a concentration- and time-dependent manner, with IC₅₀ values being 43 μM and 31 μM at pH 6.4 and 7.4, respectively. YJA20379-5, given intraduodenally, had a potent inhibitory effect on the gastric acid secretion in pylorus-ligated rats. The ED₅₀ value for acid secretion was 15.4 mg/kg. YJA20379-5, administered orally, also suppressed gastric damages induced by water-immersion stress, indomethacin and ethanol, and duodenal damage induced by mepirizole in rats; the ED₅₀ values were 17.6, 4.7, 3.0 and 18.7 mg/kg, respectively. Furthermore, repeated oral administration of YJA20379-5 accelerated the spontaneous healing of acetic acid-induced gastric ulcers in rats. It is concluded that the antisecretory activity of YJA20379-5 appears to be associated with inhibition of H⁺,K⁺-ATPase, while its antigastric and antiduodenal lesion activities are primarily related to the antisecretory effect.     

Pantoprazole: a new and more specific proton pump inhibitor

Pantoprazole is the third proton pump inhibitor (PPI) to be launched for the treatment of acid-peptic diseases. Like other drugs in this class, pantoprazole causes long-lasting inhibition of acid secretion by inactivating the parietal cell H+/K+-ATPase. Compared with H2 antagonists, pantoprazole results in faster pain relief, more rapid ulcer healing, healing of resistant ulcers and far greater efficacy in oesophageal reflux disease. The three PPIs currently available display almost identical efficacy in the treatment of acid-peptic diseases and when included as part of Helicobacter pylori eradication regimes. However, pantoprazole shows improvements in selectivity and pharmacokinetic properties compared with omeprazole and lansoprazole. The bioavailability of pantoprazole is considerably higher than omeprazole, remains constant upon repeated dosing, and is unaffected by food. Significantly, pantoprazole does not influence hepatic cytochrome P450 activity and does not therefore interact with co-administered drugs. This is in contrast to omeprazole, which inhibits P450, and lansoprazole, which appears to weakly induce multiple metabolic pathways. Although pantoprazole is entering an antisecretory market dominated by omeprazole and ranitidine, it has a number of potential advantages. In this respect it is worth recalling that enhanced specificity and the absence of drug interactions were decisive factors in determining market share in the H2 antagonist era. Pantoprazole may therefore achieve significant market penetration, particularly at the expense of lansoprazole and the H2 blockers.     

新质子泵抑制剂吡美拉唑合成与表征

目的探究吡美拉唑的合成与表征。方法分别以廉价的2,3-二甲基吡啶和2,6-二氯吡啶为起始原料,制备了关键中间体2-氯甲基-4-(3-甲氧基丙氧基)-3-甲基吡啶盐酸盐和2-巯基-5-甲氧基咪唑[4,5-b]吡啶,进而得到了吡美拉唑。结果与结论目标产物吡美拉唑及部分中间体的化学结构经红外光谱、高分辨质谱和~1H-NMR以及~(13)C-NMR确证,与文献方法相比,该路线原料易得,操作简便,避开使用2,3-二甲基-4-氯吡啶-N-氧化物为原料,进而避开了高危险试剂氢化钠,相对于文献报道的路线,收率明显提高,适合工业化生产。     

Pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats.

The pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats was investigated following intravenous administration of the drug. Mean residence time and steady state volume of distribution were 23-36 min and 0.20-0.311 kg-1, respectively, and were dose independent at the dose of 0.3-3 mumole kg-1. Total body clearance of 8.2 ml min-1 kg-1 over 0.3 mumole kg-1 was slightly increased to 11.3 ml min-1 kg-1 at 3 mumole kg-1. Renal clearance was also increased with the increase of the dose, while hepatobiliary clearance was substantially constant. Ambenonium was highly concentrated in the liver, kidney, spleen, and lung. About 30 per cent of the dose is concentrically stored in the liver at 6 h after administration, and had not disappeared after 24 h.     

质子泵抑制剂点评模式及制度的建立与效果分析

目的探讨质子泵抑制剂专项点评的有效性,建立长效机制以促进质子泵抑制剂的合理使用。方法建立质子泵抑制剂处方点评表格、点评模式、制度,对2014年及2015年7-12月使用了质子泵抑制剂的出院病历进行随机抽样,各抽取200份,共400份病历进行点评,对质子泵使用率、使用强度、合理率、平均分进行对照研究。结果从2014年实施质子泵抑制剂专项点评模式后,质子泵抑制剂使用强度从2014年的67.78下降到60.65,合理率从2014年的31.5%上升到43.0%、处方平均分从51.99提高到74.19。与2014年相比,质子泵抑制剂不合理使用情况均有下降,无适应证、无指征预防用药等一票否决缺陷及重度缺陷下降最为明显。结论质子泵抑制剂处方专项点评模式的建立与实施,促进了质子泵抑制剂的合理使用,可作为质子泵抑制剂的临床应用管理的长效机制。     

Determination of a new reversible proton pump inhibitor,DBM-819, in human plasma and urine,and rat tissue homogenates by high-performance liquid chromatography

A high-performance liquid chromatographic (HPLC) method was developed for the determination of a new proton pump inhibitor, DBM-819, in human plasma and urine and rat tissue homogenates using KR-60461 as an internal standard. A 100-microl aliquot of acetonitrile (containing 0.5 microg/ml of the internal standard) and a 200-microl aliquot of 0.1 M Na(2)HPO(4) (adjusted pH 11 with 1 N NaOH) were added to a 100-microl aliquot of biological sample. After vortex-mixing, the mixture was extracted with 1 ml of ethylacetate. After centrifugation at 12000 x g for 3 min, the organic layer was collected and evaporated under nitrogen gas. The residue was then reconstituted with a 100-microl aliquot of mobile phase, and a 40-microl aliquot was injected onto the HPLC column. The mobile phase, 0.02 M phosphate buffer (pH 5): acetonitrile: methanol (46:44:10, v/v/v), was run at a flow rate of 0.5 ml/min and the column effluent was monitored by the fluorescence detector set at an excitation wavelength of 340 nm and an emission wavelength of 470 nm. The retention times for DBM-819 and the internal standard were approximately 10.5 and 12 min, respectively. The detection limits of DBM-819 in human plasma and urine, and rat tissue homogenates were 0.01, 0.02 and 0.02 (or 0.05) microg/ml. respectively. The coefficients of variation (CV) of the assay were below 11% for human plasma and urine, and rat tissue homogenates. No interferences from endogenous substances were found.     

Antacids have no influence on the pharmacokinetics of rabeprazole, a new proton pump inhibitor, in healthy volunteers.

AIM: This randomized, open-label, crossover study was conducted to evaluate the effect of a single dose of antacid, aluminum and magnesium hydroxide suspension, on pharmacokinetics of rabeprazole in healthy male volunteers. SUBJECTS AND METHODS: Twelve subjects were randomly divided into 6 groups of 2 subjects each, and received 20 mg of rabeprazole either without antacid, concomitantly with antacid, or one hour after administration of antacid in three experimental arms with washout period of one week. The concentrations of rabeprazole in plasma were determined by high performance liquid chromatography. RESULTS: Rabeprazole was well tolerated at the 20 mg dose level when given with or without antacid. The pharmacokinetic parameters, Cmax, t(max), AUC and t1/2, showed no statistically significant differences when rabeprazole was administered alone, concomitantly with antacid or one hour after antacid administration. CONCLUSION: No influence of single dose of antacid on pharmacokinetics of rabeprazole was observed.