There have been few reports concerning to the drug-drug interactions (DDIs) with OTC drugs although an increase in the use of OTC drugs in recent years. This current study was conducted to clarify the DDIs through CYP3A inhibition by oxethazaine (OXZ), an antacid available as an OTC drug. Midazolam (MDZ) was used as a probe drug for CYP3A activity. In an in vivo study, a single oral dose of OXZ (50 mg/kg) was administered to rats 30, 60, or 120 min before oral MDZ administration (15 mg/kg). Serum concentrations of MDZ were analyzed by HPLC, and its pharmacokinetic parameters were compared with a water-treated control group. The inhibitory effect of OXZ on MDZ 1′-hydroxylation (MDZ 1′-OH) activity was investigated in vitro using rat liver and intestinal microsomes. Pretreatment of OXZ 120 min before MDZ administration significantly increased the area under the serum concentration-time curve (AUC 0-∞ ) of MDZ six-fold compared to the control group without a change in elimination half-life (t 1/2 ). In contrast, OXZ pretreatment 30 or 60 min before MDZ administration did not show any remarkable change in MDZ pharmacokinetic parameters. The in vitro study showed that OXZ inhibited MDZ 1′-OH activity in a concentration-dependent manner both in liver and intestinal microsomes. These results suggested that OXZ increases serum MDZ concentration presumably by the inhibition of liver and/or intestinal CYP3A activity. OXZ was predicted to cause the DDIs mediated by CYP3A inhibition, although this effect depended on the dose interval.

OTC drugs have an important role in self-medication. However, the pharmacokinetic properties of some OTC drugs have not been fully investigated and reports concerning their drug interactions are insufficient. Several gastrointestinal drugs are available as OTC drugs. Because of their pharmacological properties, these drugs are often used concomitantly with other drugs. Therefore, it is important to predict the possible drug interactions among these drugs. In the current study, we investigated the inhibitory effects of five gastrointestinal drugs, namely loperamide, oxethazaine, papaverine, pirenzepine, and trimebutine, on CYP activities in human liver microsomes. Furthermore, we calculated the ratio of the intrinsic clearance of each CYP substrate in the presence or absence of the gastrointestinal drugs. The possibility of drug interactions in vivo was predicted by cut-off criteria. CYP3A4 activity was markedly inhibited by trimebutine, papaverine, and oxethazaine. Their inhibitory properties were competitive and the K i values were 6.56, 12.8, and 3.08 µM, respectively. Alternative R values of CYP3A4 exceeded the cut-off level. These results suggested that drug interactions mediated by CYP3A4 may occur during treatment with these gastrointestinal drugs, necessitating the confirmation of the clinical significance of these drug interactions to prevent unexpected adverse effects. Key words gastrointestinal drug; OTC drug; drug interaction; CYPIn recent years, people have become increasingly interested in their own health due to a rapidly aging society and/or the increase of lifestyle-related diseases. As a result, the concept of self-care, which includes self-medication, has attracted popular attention. Self-medication is defined as the selection and use of medicines by individuals to treat self-recognized illnesses or symptoms. 1) Self-medication includes the use of OTC drugs under the advice of healthcare professionals such as pharmacists.2) Therefore, OTC drugs play an important role in self-medication. OTC drugs are considered relatively safer than ethical drugs. However, many OTC drugs, especially those developed in the distant past, have not had their pharmacokinetic properties sufficiently studied. They may be safe to use alone; however, there is no evidence to suggest their safety when combined with other drugs.Many drug interactions affect specific metabolic processes, especially those mediated by CYP. CYP-mediated drug interactions are roughly classified into enzyme inhibition and enzyme induction. Most are based on enzyme inhibition, with many documented clinically significant cases. Therefore, it is important to examine whether OTC drugs have inhibitory effects on CYP activity.A recent study reported that diphenhydramine interacted with metoprolol via CYP2D6 inhibition.3) Diphenhydramine potently inhibited metoprolol α-hydroxylation in vitro. Moreover, a clinical study found that diphenhydramine decreased metoprolol metabolic clearance 2.5-fold in CYP2D6 extensive metabolizers.4) Diphenhydramine, a fir...

A 35-year-old woman with fever, edema and rash was admitted. Pleural effusion and cardiomegaly were observed. A laboratory analysis revealed anemia with iron deficiency and elevated human parvovirus B19 (B19V) immunoglobulin M. The patient's hepcidin-25 and erythroferrone levels were not elevated compared to those observed later in her clinical course. On the other hand, her growth differentiation factor-15 (GDF-15) levels were elevated. She was diagnosed to have heart failure symptoms and anemia with specific iron metabolism abnormalities due to a B19V infection. After providing supportive treatment, the heart failure symptoms disappeared and her anemia had improved. This case emphasizes the need to include a B19V infection in the differential diagnosis when we encounter cases demonstrating reversible heart failure with anemia.

No abstract

No abstract