Simultaneous quantification of tegoprazan and its major metabolite M1 in dog plasma using liquid chromatography-tandem mass spectrometry.

Tegoprazan is a novel potassium-competitive acid blocker (P-CAB) recently approved in Korea as a next-generation therapeutics for gastric acid-related diseases. In the present study, we demonstrate a simple bioanalytical liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of tegoprazan and its major metabolite (M1) in dog plasma. The developed method is based on protein precipitation and LC-MS/MS, validated according to the regulatory guidance for bioanalytical method validation. The calibration curves were linear in the concentration range of 50 ng/mL-50 µg/mL and 5 ng/mL-5 µg/mL for tegoprazan and M1, respectively. The inter- and intra-day precisions were evaluated with a coefficient of variation of <15%, and the mean accuracy ranged 92.6%-105%. The method exhibited good sensitivity and specificity. The stability of bench-top (for 8 h), freeze-thaw (3 cycles), and processed-samples (for 24 h at 4 °C) was acceptable. Tegoprazan was stable in dog plasma for 6 weeks at -70 °C. In conclusion, we successfully established a method for the simultaneous quantification of tegoprazan and M1 in dog plasma, and the method was validated for specificity, sensitivity, linearity, matrix effects, recovery, accuracy, precision, and stability. Finally, we show that the method was successfully applied to a pharmacokinetic study in dogs.

Drug Interactions with the Direct-Acting Antiviral Combination of Ombitasvir and Paritaprevir-Ritonavir.

The two direct-acting antiviral (2D) regimen of ombitasvir and paritaprevir (administered with low-dose ritonavir) is being developed for treatment of genotype subtype 1b and genotypes 2 and 4 chronic hepatitis C virus (HCV) infection. Drug-drug interactions were evaluated in healthy volunteers to develop dosing recommendations for HCV-infected subjects. Mechanism-based interactions were evaluated for ketoconazole, pravastatin, rosuvastatin, digoxin, warfarin, and omeprazole. Interactions were also evaluated for duloxetine, escitalopram, methadone, and buprenorphine-naloxone. Ratios of geometric means with 90% confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve were estimated to assess the magnitude of the interactions. For most medications, coadministration with the 2D regimen resulted in a <50% change in exposures. Ketoconazole, digoxin, pravastatin, and rosuvastatin exposures increased by up to 105%, 58%, 76%, and 161%, respectively, and omeprazole exposures decreased by approximately 50%. Clinically meaningful changes in ombitasvir, paritaprevir, or ritonavir exposures were not observed. In summary, all 11 medications evaluated can be coadministered with the 2D regimen, with most medications requiring no dose adjustment. Ketoconazole, digoxin, pravastatin, and rosuvastatin require lower doses, and omeprazole may require a higher dose. No dose adjustment is required for the 2D regimen.

Effect of food or antacid on pharmacokinetics and pharmacodynamics of febuxostat in healthy subjects.

UNLABELLED: What is already known about this subject. Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase. What this study adds. This is the first manuscript to address the effect of food and antacid on the pharmacokinetics and/or pharmacodynamics of febuxostat. The study will determine whether the drug can be administered regardless of food or antacid. It will therefore influence how the drug should be administered. AIMS: To evaluate the effects of food or antacid on the pharmacokinetics and/or pharmacodynamics of febuxostat. METHODS: Four Phase I, two-period, crossover studies were performed in healthy male and female subjects. Subjects either received single 40-mg (n = 24), multiple 80-mg (n = 24) and single 120-mg (n = 20) doses of febuxostat in fasting and nonfasting conditions, or received single 80-mg (n = 24) doses alone or with antacid. RESULTS: Food caused a decrease in C(max) (38-49%) and AUC (16-19%) of febuxostat at different dose levels following single or multiple oral dosing with febuxostat. However, a slightly greater percent decrease in serum uric acid concentrations (58% vs. 51%) after multiple dosing with 80 mg of febuxostat under nonfasting conditions was observed, which was statistically (P < 0.05) but not clinically significant. Antacid caused a decrease in C(max) (32%), but had no effect on AUC of febuxostat. Febuxostat was safe and well tolerated in all studies. CONCLUSIONS: Even though food caused a decrease in the rate and extent of absorption of febuxostat, this decrease was not associated with a clinically significant change in febuxostat pharmacodynamic effect. Despite a decrease in the absorption rate of febuxostat, antacid had no effect on the extent of febuxostat absorption. Therefore, febuxostat can be administered regardless of food or antacid intake.

Acid suppressive therapy and the effects on protease inhibitors.

OBJECTIVE: To review the literature associated with the pharmacokinetic interaction between protease inhibitors (PIs) and acid suppressive therapies and to characterize the impact of this interaction on virologic and immunologic outcomes. DATA SOURCES: A MEDLINE search (1966-October 2006) was conducted using the names of the 10 PIs and specific acid suppressive therapies including antacids, histamine(2)-receptor antagonists, and proton pump inhibitors. Abstracts and poster presentations from recent HIV/AIDS meetings were reviewed for relevance. References from retrieved articles, as well as product packaging and manufacturer information, were evaluated. STUDY SELECTION AND DATA EXTRACTION: Pertinent pharmacokinetic, immunologic, and virologic studies, in healthy and HIV-infected patients, evaluating the use of a PI and acid suppressive therapy were reviewed. DATA SYNTHESIS: Potential interactions between concomitant acid suppressive therapy and PIs were evaluated. Available information indicates that indinavir and atazanavir require an acidic gastric medium for adequate absorption. Indinavir pharmacokinetic parameters are variable with acid suppressive therapy but primarily result in decreased oral absorption. This interaction abates with concurrent ritonavir use. No immunologic or virologic data are available regarding the concomitant use of indinavir and acid suppressive therapy. The minimum concentration of atazanavir, area under the concentration-time curve, and maximum concentration are significantly reduced when used concurrently with acid suppressive therapy. Atazanavir 300 or 400 mg boosted with ritonavir 100 mg increases plasma concentrations when used with acid suppressive drugs. Virologic and immunologic outcomes appear stable when boosted atazanavir is used in HIV-positive patients. Atazanavir therapeutic monitoring should be considered when used in combination with acid suppressive therapy. CONCLUSIONS: Of the PIs reviewed, significant pharmacokinetic interactions exist between acid suppressive therapy and indinavir or atazanavir. These PIs should be used with low-dose ritonavir if acid suppressive therapy is necessary.

Acute hypermagnesemia: a rare complication of antacid administration after bone marrow transplantation.

INTRODUCTION: We reported a case of hypermagnesemia in whom hypotension, hypothermia, and coma developed after repetitive doses of a seemingly harmless antacid for epigastric pain following bone marrow transplantation. METHODS: For this case, serial electrolytes, blood urea nitrogen, creatinine, calcium, and magnesium were obtained. Issues addressed were the restoration of normal hydration by normal saline, together with forced diuresis to hasten the renal excretion of magnesium, and eventual changes in its levels. RESULTS: The highest measured magnesium concentration was 5.9 mmol/l. She recovered without dialysis. The patient's condition improved with intravenous doses of calcium gluconate, saline solution infusion, and cardiovascular support. CONCLUSION: Hypermagnesemia is rare in allogeneic stem cell recipients receiving cyclosporine therapy for prevention of acute graft-vs.-host disease (GVHD). A posttransplant status with possible GVHD, poor nutritional intake, impaired intestinal absorption, dehydration, and the use of aluminum magnesia oral suspension may have resulted in magnesium imbalance. This case report highlights several associated nonrenal risk factors for hypermagnesemia, which include gastrointestinal tract disease, dehydration, and concomitant medications, particularly, the antacids that contain magnesium.

Rapid effect of lansoprazole on intragastric pH: a crossover comparison with omeprazole.

BACKGROUND: The time to onset of acid inhibition is considered an important factor when treating patients with reflux symptoms. This study was therefore designed to investigate the effect of 30 mg lansoprazole and 20 mg omeprazole on gastric pH after single-dose administration. METHODS: The study was of a randomized, open-label, single-dose and two-way crossover design with a washout period of at least 7 days in between. Fifteen healthy adult male and female subjects were included. The subjects were intubated with a pH catheter. Intragastric pH was measured every 4th sec for 10 min before and during 8 h after drug administration. Blood samples, for determination of plasma concentrations of lansoprazole and omeprazole, were obtained on 10 occasions during 6 h after drug administration. The area under the curve (AUC), the elimination halflife (t1/2), and the peak concentration (Cmax) of the two drugs were calculated. RESULTS: All subjects completed the study without major complications. The mean pH (0-8 h) after drug administration was 2.9 for lansoprazole and 2.0 for omeprazole (P = 0.0058). A pH of more than 4 was reached for the first time after 130 min with lansoprazole and after 250 min with omeprazole. AUC was 4919 +/- 2526 nmol/l x h for lansoprazole and 1352 +/- 1120 nmol/l x h for omeprazole. CONCLUSION: Single-dose administration of 30 mg lansoprazole is followed by a rapid absorption of the drug and hence a more efficient acid suppression than after single-dose administration of 20 mg omeprazole in healthy volunteers.

Influence of the antacid Maalox and the H2-antagonist cimetidine on the pharmacokinetics of cerivastatin.

The possible influence of Maalox 70, an antacid based on magnesium-aluminum hydroxide, and the H2-antagonist cimetidine, both commonly prescribed in hypercholesterolemic patients, on the pharmacokinetics of the new HMG-CoA reductase inhibitor cerivastatin was investigated in 2 separate studies in 8 healthy young male subjects each. Cerivastatin plasma concentration/time profiles were assessed by a specific HPLC assay; in addition, total immunoreactive drug (cerivastatin plus metabolites) was determined by RIA. Single oral doses of 200 micrograms cerivastatin were administered under fasting conditions without or with 10 ml Maalox 70 suspension. The mean AUC and Cmax ratios (combined dosing/monodosing) including 90% confidence intervals were 0.92 (0.73-1.15) and 0.89 (0.72-1.10) for the HPLC data, and 0.99 (0.85-1.14) and 1.03 (0.82-1.30) for the RIA data, respectively. Thus, no interaction of the simultaneous administration of Maalox 70 on the pharmacokinetics of cerivastatin was observed. In a similar controlled, randomized nonblind 2-way crossover design the influence of the H2- antagonist and well-known cytochrome P450 enzyme inhibitor cimetidine was investigated. Eight healthy young male volunteers received single oral doses of 200 micrograms cerivastatin alone or on the fourth day of a 4-day cimetidine 400 mg b.i.d. pretreatment. The mean AUC and Cmax ratios (combined dosing/monodosing) including 90% confidence intervals were 0.98 (0.90-1.08) and 0.91 (0.78-1.07) for the RIA data, and 0.89 (0.82-0.96) and 0.93 (0.80-1.09) for the HPLC data, respectively, clearly indicating that cimetidine and cerivastatin did not interact pharmacokinetically. These results do not only reflect the apparent insensitivity of cerivastatin absorption to possible changes in gastric pH, but demonstrate that the metabolic pathways of cerivastatin, involved in its first-pass metabolism and elimination, are rather insensitive to cytochrome P450 enzyme inhibition induced by cimetidine.

Absence of gastrointestinal absorption or urinary excretion of aluminium from an allantoinate complex contained in two antacid formulations in patients with normal renal function.

We studied the plasma and urinary excretion levels of aluminum (Al) on day 0, 10 and 30 in 79 patients with gastrointestinal symptoms and normal renal function who were receiving a complex based on Al allantoinates [C4H5N4 O3 Al (OH)2] and [C4H5N4 O3 Cl Al2 (OH)4]. We evaluated the extent of Al absorption after repeated administration of this complex in two antacid formulations, Ulfon Lyoc in lyophilised tablet form (group 1; n = 40) and Ulfon suspension (group 2; n = 39). The total Al load for each antacid and patient was 512 mg daily for a total of 15360 mg during the 30-day treatment. No significant rise in plasma Al concentration was noted with either formulation between day 0 and 10, day 0 and 30 or day 10 and 30, nor was there any significant increase in urinary excretion levels. Al absorption was not increased and no toxic effects were noted, indicating that such formulations are suitable for long-term therapy in patients with gastrointestinal symptoms.

Is hypocitraturia associated with phosphaturia--a potential cause of calcium urolithiasis in first-time stone formers.

The serum and 24 hour urinary excretion levels of various lithogenic and inhibitory substances were assessed in 24 male patients with calcium stone and no previous history of urolithiasis and in 19 age-matched controls. Two groups did not differ significantly (P < 0.01) except in the excretions of sodium, citric acid (being higher in normals) and inorganic phosphate (being higher in patients). Fifty percent patients had hyperphosphaturia, 29.2% hypocitraturia, 20.8% hyperoxaluria and 16.7% hypercalciuria. The present data suggests that hypocitraturia in association with phosphaturia might be one of the main risk factors responsible for calcium urolithiasis in this area.

Effect of oral aluminium citrate on short-term tissue distribution of aluminium.

Aluminium (Al) concentrations in the plasma, bone, lung, liver, kidney, spleen, duodenum and brain of rats were measured 2, 4 and 24 hr after a single oral dose of 0.46 mmol as Al citrate (1:5 molar ratio). Compared with control animals, very high concentrations were found at 2 hr post-administration in plasma (539 micrograms/litre) and in all tissues except the brain where Al did not change throughout the 24-hr period. The increased levels in the liver (161 ng/g) and lung (89.7 ng/g) at 2 hr were maintained until 4 hr and then decreased. At 24 hr the plasma value decreased to 24.6 micrograms/litre as compared with the peak value of 539 micrograms/litre. In a typical soft tissue such as the kidney the peak at 2 hr of 682 ng/g decreased to 241 ng/g, which was still more than 10-fold greater than the control level. Uniquely, in the case of bone Al increased throughout the period of the experiment. Our results indicate that Al in the citrate form is readily absorbed and that it appears to equilibrate rapidly between plasma and the intracellular compartments of most soft tissues but does not readily permeate the blood-brain barrier. In a group of rats previously given silicic acid in the drinking water and co-administered with the Al dose, the tissue Al distribution pattern at 4 hr post-administration was modified in comparison with the test animals not loaded with silicic acid. Al concentrations in plasma and soft tissues were significantly reduced except for the spleen, in which Al increased, and there was complete inhibition of the very high Al uptake/deposition in bone.

Aluminum speciation studies in biological fluids. Part 3. Quantitative investigation of aluminum-phosphate complexes and assessment of their potential significance in vivo.

Following the discovery that specific health disorders affecting patients with renal disease were due to their excessive body accumulation of aluminum, it was established that aluminum toxicity was mainly due to the ingestion of aluminum-containing phosphate binders. Suspicion of toxicity was thus cast on aluminum-containing antacids, and subsequent tests held on healthy subjects did reveal that aluminum hydroxide gels were also potential oral sources of aluminum, especially in the presence of citric acid. Nevertheless, authors of these tests concluded that there was only marginal absorption of aluminum phosphate. In contrast with these clinical conclusions, it has recently been contended on theoretical grounds that aluminum phosphate represents a serious health hazard. To help elucidate this issue, this paper first deals with a quantitative investigation of aluminum-phosphate equilibria under physiological conditions. Then appropriate computer simulations based on corresponding results are used to assess the actual extent to which phosphate can influence aluminum bioavailability. These simulations confirm that aluminum phosphate is not expected to induce absorption of high amounts of aluminum when administered by itself. Nevertheless, this result may no longer apply in the presence of food, whose various acidic components are likely to modify the involved chemical equilibria. Moreover, it is shown that rising blood plasma phosphate levels should tend to increase aluminum tissue penetration and hence favor its potential toxicity.

[Pharmacokinetic interaction of cefixime and 2 antacids. Preliminary results]. / Etude de l'interaction pharmacocinétique entre le céfixime et deux antiacides. Résultats préliminaires.

A crossover study was undertaken in 8 healthy volunteers to evaluate the pharmacokinetics of cefixime administered orally alone or combined with an antacid. Each subject received successively: cefixime alone, Maalox followed 30 min later by cefixime, then Maalox followed 4 hours later by cefixime and finally Alka-Seltzer followed 30 min later by cefixime. Sixteen blood samples were drawn from 0 to 24 hours after oral administration, and plasma cefixime parameters were determined, using a HPLC assay. Four parameters were used to detect a possible interaction: Cmax, Tmax, AUCO-N and AUCO-alpha. No significant difference was observed between the four parameters. Thus, poor absorption of cefixime when combined with an antacid can be ruled out.

Serum aluminium levels of intensive care patients treated with two different antacids for prevention of stress ulceration.

We studied the serum aluminum levels of 30 intensive care patients receiving six daily doses of magaldrate (Riopan) or aluminium hydroxide (Trigastril). In both groups we found a significant rise of the serum aluminium concentration (p less than 0.01) following administration of the antacid solutions. Examination on day 9 and 15 the magaldrate group showed significantly (p less than 0.05) lower aluminium levels than the aluminium hydroxide group. An increase up to the critical serum aluminium level of 100 ng/ml occurred in none of the patients that all had normal or slightly impaired renal function. Therefore routine measurements of serum aluminium levels in patients without renal impairment are not considered necessary following antacid therapy. However, we recommend the use of antacids with an aluminium absorption rate as low as possible.

The effects of antacids on the absorption of enteric-coated phenylbutazone (butacote).

Phenylbutazone bioavailability from an enteric-coated formulation (Butacote) has been studied in normal volunteers following ingestion of a single 200 mg dose with water, aluminium hydroxide and magnesium trisilicate. No significant alteration in bioavailability of phenylbutazone from Butacote was noted in the presence of the antacids.