Pharmacokinetic Interactions Between Tegoprazan and Naproxen, Aceclofenac, and Celecoxib in Healthy Korean Male Subjects.

PURPOSE: Tegoprazan is a potassium-competitive acid blocker used for gastric acid suppression and may be used with NSAIDs to reduce gastrointestinal adverse effects. The aim of this study was to evaluate the pharmacokinetic interaction between tegoprazan and commonly used NSAIDS, namely, naproxen, aceclofenac, and celecoxib. METHODS: An open-label, 3-cohort, randomized, multiple-dose, 3-way crossover study was conducted in healthy male subjects. In cohort 1, tegoprazan (50-mg tablet, once daily) and naproxen (500-mg tablet, twice daily) were administered separately or concurrently for 7 days in each period. In cohort 2, tegoprazan and aceclofenac (100-mg tablet, twice daily) were administered separately or concurrently for 7 days in each period. In cohort 3, tegoprazan and celecoxib (200-mg capsule, twice daily) were administered separately or concurrently for 7 days in each period. Pharmacokinetic blood samples were collected up to 24 hours after the last dose. FINDINGS: Seventeen subjects from cohort 1, sixteen subjects from cohort 2, and thirteen subjects from cohort 3 were included in the pharmacokinetic analysis. In cohort 1, the geometric least squares mean ratios (90% CIs) for AUCτ (AUC profiles over the dosing interval) and Css,max (Cmax at steady state) were 1.01 (0.91-1.12) and 0.99 (0.83-1.17) for tegoprazan, and 1.00 (0.97-1.03) and 1.04 (0.99-1.09) for naproxen, respectively. The values in cohort 2 were 1.03 (0.93-1.13) and 0.94 (0.86-1.04) for tegoprazan, and 1.06 (1.00-1.12) and 1.31 (1.08-1.60) for aceclofenac. The values in cohort 3 were 1.01 (0.86-1.18) and 1.02 (0.87-1.19) for tegoprazan, and 1.08 (0.96-1.22) and 1.18 (0.97-1.43) for celecoxib. IMPLICATIONS: Changes in the maximum aceclofenac or celecoxib concentrations were detected after concurrent administration with tegoprazan, which were considered mainly due to the pharmacodynamic effect of tegoprazan. Because systemic drug exposure (shown as AUCτ) was unchanged after concurrent administration of any 3 NSAIDs with tegoprazan, the increase in aceclofenac or celecoxib Css,max when administered with tegoprazan would not be clinically significant in practice. CLINICALTRIALS: gov Identifier: NCT04639804.

Effect of meal timing on pharmacokinetics and pharmacodynamics of tegoprazan in healthy male volunteers.

Tegoprazan, a novel potassium-competitive acid blocker, is used to treat acid-related diseases. However, there is no information on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the marketed dosage of tegoprazan under various meal timings in a fed and fasted state. The study aimed to assess the effect of meal timing on PKs and PDs of tegoprazan 50 mg after a single administration in healthy male subjects. An open-label, single-dose, three-treatment, three-period crossover study was conducted. A total of 12 subjects were orally administered a single dose of tegoprazan 50 mg among various conditions: in a fasted state, at 30 min before or 30 min after a high-fat meal. PK parameters were estimated by the noncompartmental method. Continuous 24-h intragastric pH monitoring was done for PD analysis. The PKs and PDs of tegoprazan were compared among the various meal timings. Compared with the fasting condition, the PK profile of tegoprazan was similar when administered 30 min before a high-fat meal; however, delayed absorption with similar systemic exposure was observed when administered 30 min after a high-fat meal. The magnitude of acid suppression evaluated through the PD parameters increased when administered 30 min after a high-fat meal compared with fasting the condition and when administered 30 min before a high-fat meal. However, the increased difference in acid suppression was not clinically significant. Meal timing had no clinically significant effect on the PKs and PDs of tegoprazan 50 mg. Therefore, the marketed dosage of tegoprazan could be administered regardless of the meal timing. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tegoprazan, a novel potassium-competitive acid blocker, is used to treat acid-related diseases. WHAT QUESTION DID THIS STUDY ADDRESS? This study evaluated the effect of food on pharmacokinetics (PKs) and pharmacodynamics (PDs) of tegoprazan under various mealtime conditions. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study showed that delayed absorption of tegoprazan was observed at "after meal condition," however, the amount of systemic exposure of "after meal condition" was similar to "fasting condition" and "before meal condition." In addition, gastric acid suppression of tegoprazan was similar between fasting condition and before meal condition, whereas increased gastric acid suppression was observed at after meal condition. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? In the actual clinical environment, patients take medicine under various fed conditions. This study evaluated the effect of food on PKs and PDs of tegoprazan in various clinical conditions, and provided the important information about meal timing when administering tegoprazan.

Optimized liquid chromatography-tandem mass spectrometry for Otaplimastat quantification in rat plasma and brain tissue.

An optimized liquid chromatography-tandem mass spectrometry method for simple and sensitive quantification of Otaplimastat in rat plasma and brain tissue was developed and validated. Protein precipitation with acetonitrile was selected for sample preparation method based on recovery and matrix effect. The chromatographic separation of the sample was performed on a reverse-phase AQ column with an isocratic mobile phase consisting of 10 mM ammonium acetate (pH 4.0) and acetonitrile (50:50, v/v). The analyte was quantified by multiple reaction monitoring with a Waters Quattro micro™ API mass spectrometer. The lower limits of quantification were 20 ng/mL in plasma and 2 ng/g in brain, with the relative standard deviation % of 7.6 and 8.0% for plasma and brain samples, respectively. Acceptable intra-day and inter-day precisions and accuracies were obtained. Otaplimastat was sufficiently stable under all relevant analytical conditions, including a temperature of 4°C for 24 hr, room temperature 20°C for 24 hr, -80°C for 10 days and three freeze-thaw cycles (each at -80°C for 24 hr), for rat plasma and brain tissue. The validated method was successfully used to measure Otaplimastat concentrations in rat plasma and brain samples.

High-Dose Metformin May Increase the Concentration of Atorvastatin in the Liver by Inhibition of Multidrug Resistance-Associated Protein 2.

In this study, we evaluated the effect of coadministered metformin on the biliary excretion and liver concentration of atorvastatin. To investigate the inhibitory effect of metformin on biliary efflux transporters, the transport of atorvastatin in MDCKII-MDR1, BCRP, and MRP2 was evaluated. The effects of metformin on the steady state liver concentration and biliary excretion of atorvastatin and 2-hydroxyatorvastatin were evaluated in SDR and Mrp2-deficient EHBR. Metformin did not inhibit the transport of atorvastatin via BCRP and MDR1. However, metformin significantly inhibited the transport of atorvastatin and 2-hydroxyatorvastatin via MRP2 (apparent IC50 = 12 and 2 µM). Coadministered metformin significantly increased the Kp,liver and Cliver (1.7- and 1.6-fold) and decreased the biliary clearance of atorvastatin (2.7-fold) in SDR, but it did not affect the plasma concentration and total clearance of atorvastatin. Similar effects by metformin were observed for 2-hydroxyatorvastatin. In addition, coadministered metformin did not have any effect in EHBR. Therefore, coadministered metformin increases the liver concentration of atorvastatin via inhibition of the Mrp2 in rats, without affecting the plasma concentration. This "silent interaction" by metformin in atorvastatin and metformin combination therapy may be related to the unnoticeable pharmacological synergism or unpredicted side effects of atorvastatin in the liver.

Phenylvinylcobalamin: an alkenylcobalamin featuring a ligand with a large trans influence.

Cob(I)alamin reacts with phenylacetylene to produce two diastereomers in which the organic ligand is coordinated to the upper (ß) and lower (α) face of the corrin ring, respectively. The isomers were separated chromatographically and characterised by ESI-MS and, in the case of the ß isomer, by (1)H and (13)C NMR. Only the ß isomer crystallised and its molecular structure, determined by X-ray diffraction, shows that the organic ligand coordinates Co(III) through the ß carbon of the phenylvinyl ligand. The Co-C bond length is 2.004(8) Å while the Co-N bond length to the trans 5,6-dimethylbenzimidazole (dmbzm) base is 2.217(8) Å, one of the longest Co-Ndmbzm bond lengths known in an organocobalamin. Unlike benzylcobalamin (BzCbl), phenylvinylcobalamin (PhVnCbl) is stable towards homolysis. DFT calculations (BP86/TZVP) on model compounds of BzCbl and PhVnCbl show that the Co-C bond dissociation energy for homolysis to Co(II) and an organic radical in the former is 8 kcal mol(-1) lower than in the latter. An analysis of the electron density at the Co-C bond critical point using Bader's QTAIM approach shows that the Co-C bond in PhVnCbl is shorter, stronger and somewhat more covalent than that in BzCbl, and has some multiple bond character. Together with calculations that show that the benzyl radical is more stable than the phenylvinyl radical, this rationalises the stability of PhVnCbl compared to BzCbl. The phenylvinyl ligand has a large trans influence. The pKa for deprotonation of dmbzm and its coordination by the metal in ß-PhVnCbl is 4.60 ± 0.01, one of the highest values reported to date in cobalamin chemistry. The displacement of dmbzm ligand by CN(-) in ß-PhVnCbl occurs with log K = 0.7 ± 0.1; the trans influence order of C-donor ligands is therefore CN(-) < CCH < CHCH2 = PhVn < Me < Et.