Comparison of the Effects of Omeprazole and Rabeprazole on Ticlopidine Metabolism In Vitro

Abstract

Abstract. The thienopyridine derivative ticlopidine (TCL) is an inhibitor of adenosine diphosphate-induced platelet aggregation. Combination therapy with a thienopyridine derivative and aspirin is standard after coronary stenting, although more hemorrhagic complications occur with the combination therapy than with aspirin alone. A proton pump inhibitor (PPI) is required for prevention or treatment of upper gastrointestinal bleeding in such cases. We examined the effects of PPIs [omeprazole (OPZ) and rabeprazole (RPZ)] on TCL metabolism using pooled human liver microsomes prepared from various human liver blocks and 12 individual human liver microsomes. We calculated the K i values of each PPI for TCL metabolic activity and compared the inhibitory effect of each PPI on TCL metabolism. The K i values of OPZ and RPZ were 1.4 and 12.7 μM, respectively. The inhibitory effect of OPZ (78.6 ± 0.05%) was significantly greater than that of RPZ (24.2 ± 0.05%) (P < 0.001). Interestingly, a negative correlation existed between the inhibitory effect of OPZ and CYP2C19 activity (r = −0.909, P < 0.001). These results suggest that the inhibitory effect of OPZ is more potent than that of RPZ in vitro. In conclusion, RPZ appears preferable when administering TCL, aspirin, and a PPI in combination.

Chrysophanol-8-O-glucoside, an Anthraquinone Derivative in Rhubarb, Has Antiplatelet and Anticoagulant Activities

“…The EtOAc-soluble fraction was diluted with acetone and then filtrated through filter paper to give the acetone fraction (E2, 226.1 g). The E2 (100 g) was subjected to silica gel column chromatography with the mixtures of CHCl 3 and MeOH in increasing polarity (80:1 to 0:1) to yield six fractions (E2.1 -E2.6). Emodin (220 mg) were obtained from the subfraction E2.2 by using an ODS column with MeOH-H 2 O (1:1).…”

“…Emodin (220 mg) were obtained from the subfraction E2.2 by using an ODS column with MeOH-H 2 O (1:1). The subfraction E2.3 was rechromatographed on a silica gel column with a stepwise gradient of CHCl 3 and MeOH (4:1 to 0:1) to give CP-8-O-glc (613 mg).…”

“…Furthermore, increased platelet aggregation is one of the essential contributors to the onset and development of cardiovascular diseases such as ischemic heart disease and stroke, which remain leading causes of death (1). Therefore, much research has been carried out to develop antiplatelet agents with improved efficacy to prevent and/or treat platelet hyperactivity-related cardiovascular diseases (2,3).…”

Monoester-DiterpeneAconitumAlkaloid Metabolism in Human Liver Microsomes: Predominant Role of CYP3A4 and CYP3A5

“…Pooled human liver microsomes (HLMs, 20 mg/mL, including reductase), β -nicotinamide adenine dinucleotide phosphate (NADP), glucose-6-phosphate (6-P-G), and glucose-6-phosphate dehydrogenase (PDH) were purchased from BD Gentest Corp. (Woburn, MA, USA). cDNA-expressed CYP enzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5), chemical inhibitors (fluvoxamine maleate, quercetin, amiodarone, omeprazole, quinidine, diethyldithiocarbamic acid, and ketoconazole) [22–27], and inhibitory monoclonal antibodies were also obtained from BD Gentest Corp. (Woburn, MA, USA). The monoclonal antibodies (mAbs, 10 mg/mL protein content) used were mAb-1A2 (anti-human CYP1A2), mAb-2C8 (anti-human CYP2C8), mAb-2C19 (anti-human CYP2C19), mAb-2D6 (anti-human CYP2D6), mAb-2E1 (anti-human CYP2E1), and mAb-3A4/5 (anti-human CYP3A4/5).…”

“…The selective inhibitors were chosen based on FDA recommendation, and previous reports, and are listed as follows: fluvoxamine maleate for CYP1A2, quercetin for CYP2C8, amiodarone for CYP2C9, omeprazole for CYP2C19, quinidine for CYP2D6, diethyldithiocarbamic acid for CYP2E1 and ketoconazole for CYP3A4/5 [22–27]. To obtain the maximum possible inhibition for each of the isoforms, the final inhibitor concentrations in the reaction mixtures were much higher than the reported Ki values.…”