Mosapride as a hepatic CYP3A probe in rats：compared with the reference probe midazolam

• Main Authors: Pei-HsuanJen, 任沛瑄
• Other Authors: CHEN-HSI CHOU
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/58093888886482002363

碩士 === 國立成功大學 === 臨床藥學研究所 === 98 === Introduction Cytochrome P450 3A is one of the most important CYP450 subfamilies because of its large number of xenobiotics and endogenous substrates. Considerable interindividual variability in the expression and activity of CYP3A was proved to be responsible for variability in drug response. The use of selected drugs as “probes” to assess in vivo CYP activity has been the subject of intense interest for over a decade.This approach is suggested by numerous organizations, including the US Food and Drug Administration, European Federation of Pharmaceutical Sciences, the American Association of Pharmaceutical Sciences, and the pharmaceutical industry. Among many CYP3A probes, midazolam is the most accepted CYP3A probe used in human, but it’s use is limited by being a control substance, and it’s assay difficulties. Other probes have similar problems. A more convenient, easy-used, and time-saving CYP3A probe is still required. Purpose In this project, mosapride, a new prokinetic agent, was evaluated as an in vivo probe for measuring hepatic CYP3A activity in SD rats to determine whether by the developed limited sampling strategies, it’s clearance could be used to reflect in vivo CYP3A activity. Furthermore, the relationship between the clearance of mosapride and the clearance of midazolam was examined to determine the applicability of mosapride in the CYP3A-related drug-drug interactions, such as under CYP3A induction or inhibition conditions. Methods Each male SD rats was first introduced midazolam IV infusion (infusion rate：0.02 mg/min), followed 2-hour midazolam washout period, mosapride was administered to the same rats (5 mg/kg); its plasma concentrations were followed up to 360 minutes. In the CYP3A modulation group, rats received midazolam and mosapride after pretreatment with ketoconazole or dexamethasone. All plasma samples were analyzed by a validated HPLC method. The liver was excised afer in vivo pharmacokinetic experiment for CYP3A2 content measurement. Results Mosapride could reflect CYP3A activity through it’s pharmacokinetic parameters, the clearance（CL）decreased from 58.9 to 23.1 mL/min/kg when pretreatment with ketoconazole.On the other hand, the CL increased from 58.9 to 77.4 mL/min/kg when pretreatment with dexamethasone. The same trend were also observed in the CL of midazolam. There was significant concordance between mosapride and midazolam CL（R = 0.794, P＜0.001, N=23）. Based on the data from limited sampling strategies, mosapride CL still showed strong correlation with midazolam CL. Conclusion Strong correlation between the clearances of mosapride and midazolam supports the applicability of mosapride as a probe to assess hepatic CYP3A4 activity in vivo. Mosapride plasma concentration at 120 min after a single IV mosapride dose was proved useful as a single-point determination of plasma clearance which can be reflected the total CYP3A4 activity in vivo