Characterization of human cytochrome P450 enzymes catalyzing domperidone N-dealkylation and hydroxylation in vitro

AIMS: To confirm the identity of the major metabolites of domperidone and to characterize the cytochrome P450s (CYPs) involved in their formation. METHODS: Human liver microsomes (HLMs) were used to characterize the kinetics of domperidone metabolism and liquid chromatography-mass spectrometry to identify the products. Isoform-specific chemical inhibitors, correlation analysis and expressed human CYP genes were used to identify the CYPs involved in domperidone oxidation. RESULTS: In HLMs, domperidone underwent hydroxylation to form 5-hydroxydomperidone (MIII) and N-dealkylation to form 2,3-dihydro-2-oxo-1H-benzimidazole-1-propionic acid (MI) and 5-chloro-4-piperidinyl-1,3-dihydro-benzimidazol-2-one (MII). The formation of all three metabolites (n = 4 HLMs) followed apparent Michaelis-Menten kinetics. The mean Km values for MI, MII and MIII formation were 12.4, 11.9, and 12.6 micro m, respectively. In a panel of HLMs (n = 10), the rate of domperidone (5 microm and 50 microm) metabolism correlated with the activity of CYP3A (r > 0.94; P < 0.0001). Only ketoconazole (1 microm) (by 87%) and troleandomycin (50 microm) (by 64%) inhibited domperidone (5 microm) metabolism in HLMs. Domperidone (5 and 50 microm) hydroxylation and N-dealkylation was catalyzed by expressed CYP3A4 at a higher rate than the other CYPs. CYP1A2, 2B6, 2C8 and 2D6 also hydroxylated domperidone CONCLUSIONS: CYP3A-catalyzed N-dealkylation and aromatic hydroxylation are the major routes for domperidone metabolism. The drug would be expected to demonstrate highly variable bioavailability due to hepatic, and possibly intestinal first-pass metabolism after oral administration. Increased risk of adverse effects might be anticipated during concomitant administration with CYP3A inhibitors, as well as decreased efficacy with inducers of this enzyme.     

铝碳酸镁和多潘立酮联合治疗残胃炎50例

目的评价铝碳酸镁和多潘立酮联合治疗残胃炎的疗效及安全性。方法50例患均给予铝碳酸镁1.0g，每d3次，多潘立酮10mg，每d3次，疗程4周。观察治疗前后临床症状缓解情况，胃镜下改变及药物不良反应。结果50例患治疗20d后，临床症状均明显减轻，总有效率为100％。胃镜检查残胃炎症消退，食管黏膜充血水肿明显减轻，胆汁反流控制，未见明显不良反应。结论多潘立酮能减少胃胆汁反流，铝碳酸镁可结合胆汁酸，二联合可有效缓解残胃炎的症状，是治疗残胃炎安全，有效的药物。     

Effects of long-term application of dopamine HCl on dopamine agonist-induced cAMP production in rat renal cortex

目的：观察长期给予盐酸多巴胺对大鼠肾皮质多巴胺受体亚型所介导的腺苷酸环化酶活性的影响．方法：用放免分析法测定ｃＡＭＰ含量，作为反映多巴胺受体功能的指标．结果：长期给予盐酸多巴胺可显著减少肾皮质由非诺多泮引起的ｃＡＭＰ增加的量和在Ｓｃｈ２３３９０存在下由ＰＢＤＡ引起的ｃＡＭＰ降低的量，但其变量百分比则与对照组无显著差异．Ｓｃｈ２３３９０可阻断由非诺多泮和ＰＢＤＡ引起的ｃＡＭＰ的增加，而多潘立酮可阻断在Ｓｃｈ２３３９０存在下由ＰＢＤＡ引起的ｃＡＭＰ的降低．结论：长期应用多巴胺可使大鼠肾皮质的ＤＡ１和ＤＡ２受体均发生明显的“下调”，但余留受体的反应性不变．     

光纤化学传感仪在线监测多潘立酮片溶出度

目的：考察光纤化学传感仪实时、在线过程监测多潘立酮片体外溶出度测定方法的可行性。方法：采用DT-601型光纤传感药物溶出度／释放度原位过程监测仪，同时监测6片多潘立酮片体的药溶出过程，双波长法（284／350nm）消除赋形剂干扰，计算机处理数据、实时显示药物溶出／释放曲线及打印结果，并与部颁标准WS1-（X-185）-97Z规定方法作比较。结果：本法自动监测药物溶出的全过程，实时显示完整的药物溶出曲线及数据，直接提取溶出度参数，与部颁标准方法比较，T4、T50及累积溶出百分率差异均无统计学意义（P〉0．05）。结论：光纤药物溶出度过程监测法能够有效测定药物的溶出度。免除了补液、过滤、稀释等手续，减少人为操作误差，结果准确。     

Potentiation of domperidone-induced catalepsy by a P-glycoprotein inhibitor,cyclosporin A

The distribution of domperidone (DOM), a peripheral dopamine D(2) receptor antagonist, to the brain is restricted by P-glycoprotein (P-gp) at the blood-brain barrier (BBB) and for this reason, DOM rarely causes parkinsonian symptoms, such as extrapyramidal side effects (EPS), unlike other dopamine D(2) antagonists. In this study, we aimed to investigate whether cyclosporin A (CsA), a P-gp inhibitor, potentiates EPS induced by DOM.The intensity of EPS was assessed in terms of the duration of catalepsy in mice. D(1), D(2) and mACh receptor occupancies at the striatum were measured in vivo and in vitro. Moreover, the distribution of DOM to the brain was investigated by using an in situ brain perfusion technique. The intensity of DOM-induced catalepsy was significantly potentiated by the coadministration of CsA. The in vivo occupancies of D(1), D(2) and mACh receptors, as well as the brain distribution of DOM, were increased by CsA. These results suggest that CsA increases the brain distribution of DOM by inhibiting P-gp at the BBB, and potentiates catalepsy by increasing the occupancies of the D(1) and D(2) receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA.     

Co-administration of ropinirole and domperidone during rapid dose escalation of the dopamine agonist

In patients naive to dopaminergic therapy, reducing the side-effects associated with dopamine agonist treatment will permit faster titration to effective therapeutic doses. The primary aim of this study was to compare the incidence of dopaminergic side-effects in parkinsonian patients undergoing fast titration with ropinirole under domperidone cover with that of patients undergoing slow titration with matched domperidone placebo. Patients in the former group experienced nausea on significantly fewer days than patients in the latter group. The fast-titration regimen with domperidone cover was well tolerated and allowed ropinirole to be introduced quickly.     

3厂家多潘立酮片质量比较

目的 :对3厂家多潘立酮片进行质量比较。方法 :参照卫生部部颁标准和原研发厂标准设计试验 ,就溶出度、含量均匀度、含量、有关物质、泡包装密封性等进行测定。结果 :Y、W、L3厂家各3批/次产品含量分别为98 23 %～99 74 %、96 92 %～98 31 %、97 42 %～98 72 % ;含量均匀度A +1 80S分别为2 11～3 38、3 97～5 25、5 49～7 47 ,符合《中国药典》对小剂量制剂的限度要求 ;均未检出杂质R061668 ,杂质R052211的量分别为0 004 %～0 024 %、0 029 %～0 072 %、0 003 %～0 056 % ,总杂质量分别为0 030 %～0 095 %、0 102 %～0 128 %、0 232 %～0 489 % ;45min时的溶出度分别为95 09 %～95 77 %、91 25 %～96 43 %、95 48 %～96 58 % ;Y、W厂家的泡包装密封性在实验条件下无一渗漏 ,L厂家的漏板率在38 %以上。结论 :Y厂家的产品好于W ,更优于L。     

曲美布汀治疗功能性消化不良疗效及安全性的研究

目的　比较曲美布汀与莫沙必利、多潘立酮治疗功能性消化不良的疗效及安全性。方法　将 2 0 0例功能性消化不良病人随机分为 3组 ,曲美布汀组 80例 ,予曲美布汀 10 0mg ,3次 d ;莫沙必利组 6 0例 ,予莫沙必利 5mg,3次 d ;多潘立酮组 6 0例 ,予多潘立酮 10mg ,3次 d。疗程均为 4周 ,观察症状变化情况并做对比分析。结果　总有效率曲美布汀组 87.5 % ,莫沙必利组为 90 .0 % ,多潘立酮组为 6 1.7%。曲美布汀、莫沙必利 2组疗效差异无显著意义(P >0 .0 5 ) ,曲美布汀组疗效优于多潘立酮组 (P <0 .0 1)。不良反应 :曲美布汀、莫沙必利、多潘立酮组分别为5 .0 %、8.0 %、6 .7% (P >0 .0 5 )。结论　曲美布汀治疗功能性消化不良近期疗效显著、安全性好。     

胃肠促动力药治疗功能性消化不良的成本-效果分析

目的：比较莫沙必利、西沙必利、氯波必利及多潘立酮治疗功能性消化不良的疗效与药物经济学成本。方法：将272例功能性消化不良患者，随机分成4组。A组予莫沙必利5mg，3次／d；B组予西沙必利10mg，3次／d；C组予氯波必利0.68mg，3次／d；D组予多潘立酮10mg，3次／d。均口服治疗，疗程均为4周，运用药物经济学的成本一效果分析方法进行评价。结果：4种治疗方案的成本一效果比分别为1．05，2.24，1．49，0.85。结论：A组治疗方案的效果最佳。     

情志舒与多潘立酮治疗非溃疡性消化不良的对照观察

采用中药情志舒和双咪哌酮（多潘立酮）对88例非溃疡性消化不良（NUD）患者进行对照治疗观察。结果显示，情志舒临床疗效明显优于多潘立酮，总有效率分别为96.0％、71.0％（P＜0.01）。作者认为NUD的发生与情志内伤密切相关，情志内伤是起因，胃肠运动功能障碍是后果。情志舒是根据中医学理论组成的疏肝和胃、调畅气机之方剂，对喜、怒、忧、思、悲、恐、惊七情过度引起的NUD均可调节，尤其适用于“怒伤肝”、“思伤脾”的双向调节。