RESUMEN
Guidance/guidelines on drug-drug interactions (DDIs) have been issued in Japan, the United States, and Europe. These guidance/guidelines provide decision trees for conducting metabolizing enzyme-mediated clinical DDI studies; however, the decision trees for transporter-mediated DDIs lack quantitative prediction methods. In this study, the accuracy of a net-effect mechanistic static pharmacokinetics (MSPK) model containing the fraction transported (ft) of transporters was examined to predict transporter-mediated DDIs. This study collected information on 25 oral drugs with new active reagents that were used in clinical DDI studies as perpetrators (42 cases) from drugs approved in Japan between April 2016 and June 2020. The AUCRs (AUC ratios with and without perpetrators) of victim drugs were predicted using the net-effect MSPK model. As a result, 83 and 95% of the predicted AUCRs were within 1.5- and 2-fold error in the observed AUCRs, respectively. In cases where the victims were statins in which pharmacokinetics several transporters are involved, 70 and 91% of the predicted AUCRs were within 1.5- and 2-fold errors, respectively. Therefore, the net-effect MSPK model was applicable for predicting the AUCRs of victims, which are substrates for multiple transporters.
Asunto(s)
Proteínas de Transporte de Membrana , Modelos Biológicos , Estados Unidos , Interacciones Farmacológicas , Proteínas de Transporte de Membrana/metabolismo , Transporte Biológico , JapónRESUMEN
Evaluation of the organic anion transporting polypeptide (OATP) 1B-mediated drug-drug interaction (DDI) potential is important for drug development. The focus of this study was coproporphyrin I (CP-I), an endogenous OATP1B biomarker.We investigated a new approach to OATP1B-mediated DDI prediction based on the mechanistic static pharmacokinetics (MSPK) model.The ratio of the area under the plasma concentration-time curve (AUCR) with and without co-administration of rifampicin (a typical OATP1B inhibitor) was found for CP-I and OATP1B substrate, respectively, and was then used to derive the correlation curve equation. The AUCR with and without co-administration of another OATP1B inhibitor than rifampicin was then predicted for the OATP1B substrates by substituting the AUCR of CP-I in the correlation curve equation to verify the predictability of the AUCR of the OATP1B substrates.The derived correlation curve equation between CP-I and the OATP1B substrates of the AUCRs with and without co-administration of rifampicin matched the observed AUCRs well. Regarding pitavastatin, rosuvastatin, and pravastatin, 92.9% of the predicted AUCR values were within a two-fold range of the observed values, indicating that this approach may be a good way to quantitatively predict DDI potential.
Asunto(s)
Rifampin , Biomarcadores , Coproporfirinas , Interacciones Farmacológicas , Transportador 1 de Anión Orgánico Específico del Hígado , Rifampin/farmacologíaRESUMEN
AIMS: Repeated use of nonsteroidal anti-inflammatory drugs can induce changes in the redox status, including production of reactive oxygen species (ROS), but the specific details of these changes remain unknown. Overhauser-enhanced magnetic resonance imaging (OMRI) has been used in vivo to monitor the redox status in several diseases and map tissue oxygen concentrations. We monitored the intra- and extracellular redox status in the stomach of rats with indomethacin-induced gastric ulcers using OMRI and investigated the relationship with gastric mucosal damage. RESULTS: One hour after oral administration of indomethacin (30 mg/kg), OMRI measurements in the stomach were made following nitroxyl probe administration. OMRI with the membrane-permeable nitroxyl probe, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPOL), demonstrated a redox change toward oxidation, which was reversed by a membrane-permeable antioxidant. Conversely, imaging with the impermeable probe, 4-trimethylammonium-2,2,6,6-tetramethyl-piperidine-1-oxyl (CAT-1), demonstrated little redox change. Redox imbalance imaging of a live rat stomach with indomethacin-induced gastric ulcers was produced by dual imaging of 15N-labeled TEMPOL and 14N-labeled CAT-1, in addition to imaging with another membrane-permeable 15N-labeled probe, 3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (MC-PROXYL), and 14N-labeled CAT-1. Pretreatment with MC-PROXYL suppressed gastric mucosal damage, whereas pretreatment with CAT-1 did not suppress ulcer formation. INNOVATION: OMRI combined with a dual probe is a less invasive imaging technique for evaluation of intracellular ROS production contributing to the formation of gastric ulcers in the stomach of indomethacin-treated rats, which cannot be done with other methods. CONCLUSION: This method may be a very powerful tool for characterizing the pathogenesis of various diseases and may have medical applications.
Asunto(s)
Indometacina/efectos adversos , Espectroscopía de Resonancia Magnética/métodos , Especies Reactivas de Oxígeno/metabolismo , Úlcera Gástrica/diagnóstico por imagen , Animales , Óxidos N-Cíclicos/administración & dosificación , Masculino , Imagen Molecular/métodos , Óxidos de Nitrógeno/administración & dosificación , Oxidación-Reducción , Pirrolidinas/administración & dosificación , Ratas , Marcadores de Spin , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/metabolismoRESUMEN
Reactive oxygen species (ROS) are thought to be involved in the gastric ulcer formation induced by indomethacin, a typical nonsteroidal anti-inflammatory drug. However, the location and the time course of ROS generation remain unknown. To assess the sites of ROS generation, we applied the noninvasive measurement of ROS to indomethacin-treated rats. By giving orally a membrane-permeable or impermeable probe, the spectra were collected as a function of time by in vivo 300-MHz electron spin resonance (ESR) spectroscopy. The ESR signal-decay rates of membrane-permeable probes, hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and 3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl, in the gastric mucosal region were significantly enhanced 1 h after indomethacin treatment, and they both caused the protection of ulcer formation; however, membrane-impermeable probes, carboxy- and trimethylammonium-TEMPO, which did not exhibit the enhanced signal decay, had no effect on ulcer formation. The enhanced signal decay in the gastric mucosa was suppressed by coadministration of the antioxidants tiron or dimethylthiourea with the nitroxyl probe. The results suggest that the enhanced signal-decay rates in the gastric ulcers observed by in vivo ESR are associated with protective effects. The enhanced signal decay caused by ROS generation in stomach, contributing to the ulcer formation induced by indomethacin, is also suggested to occur at the gastric mucus layer or the interface or the intracellular compartment of epithelial cells. Overall, these results show the potentials of noninvasive assessment of ROS production and the sites of damage by in vivo ESR using nitroxyl probes directed to specific subcellular regions.