Mechanistic understanding of the effect of Dengzhan Shengmai capsule on the pharmacokinetics of clopidogrel in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The Dengzhan Shengmai capsule (DZSM) is known in China for its remarkable curative effect as a treatment of cardiovascular diseases, such as coronary heart disease and ischemic stroke. DZSM is a Chinese herbal compound preparation that consists of four ingredients, including Erigeron breviscapus (Vaniot) Hand.-Mazz., Panax ginseng C.A. Mey, Ophiopogon japonicas (Thunb.) Ker-Gawl. and Schisandra chinensis (Turcz.) Baill., and was indexed in the Chinese Pharmacopoeia 2010. DZSM and clopidogrel are often co-prescribed in the clinic to prevent the recurrence of stroke or other cardiovascular and cerebrovascular diseases. However, the effect of DZSM on the pharmacokinetics of clopidogrel remains unclear. AIM OF THE STUDY: The purpose of the study is to explore the pharmacokinetics and potential interaction between DZSM and clopidogrel and the underlying mechanism. MATERIALS AND METHODS: Rats were used to investigate the effect of DZSM on the pharmacokinetics of clopidogrel and its active metabolite in vivo. The plasma concentrations were simultaneously determined using LC-MS/MS. The effects of DZSM on the P-gp-mediated efflux transport and CYP450-mediated metabolism of clopidogrel were investigated using MDCKII-MDR1 cells and rat liver microsomes, respectively. RESULTS: After pretreatment with DZSM, the Cmax and AUC0-∞ of clopidogrel increased from 0.4±0.1 to 1.7±0.6ng/mL and 0.9±0.4 to 2.0±0.2ng/mLh, respectively. The Cmax and AUC0-∞ of the derivatized active metabolite of clopidogrel decreased from 8.2±1.2 to 2.8±0.5ng/mL and 18.2±5.6 to 6.4±3.7ngh/mL, respectively. In MDCKII-MDR1 cells, the P-gp-mediated efflux transport of clopidogrel was significantly inhibited by the DZSM extract. In rat liver microsomes, DZSM inhibited clopidogrel metabolism with an IC50 of 0.02mg/mL. CONCLUSIONS: DZSM significantly affects the pharmacokinetics of clopidogrel and its active metabolite by inhibiting the P-gp-mediated efflux transport and CYP450-mediated metabolism of clopidogrel. Thus, caution is needed when DZSM is co-administered with clopidogrel in the clinic because the interaction of these drugs may result in altered plasma concentrations of clopidogrel and its active metabolite.

Toxicity studies of a bioactive protein with antithrombotic-thrombolytic activity, DLBS1033.

DLBS1033 is a bioactive protein extract containing Lumbricus rubellus and has been known to have antithrombotic/thrombolytic activity. The present study was aimed to assess the safety aspect of DLBS1033 in a preclinical setting, which included observation on toxic signs after acute and repeated administrations, and the drug's effect on prenatal development and drug interaction. In acute toxicity study, a high dose level (16.2 g/kg) of DLBS1033 was well tolerated. In subchronic toxicity study, after the doses of 270, 540 and 1080 mg/kg of DLBS1033 per day, no mortality was observed and other parameters were all observed to be normal. In prenatal developmental toxicity, no observed adverse effect level (NOAEL) of DLBS1033 was observed at a moderate dose (540 mg/kg). Coadministration of DLBS1033 with clopidogrel or aspirin did not cause gastric lesions, except when all three drugs were coadministrated. Taken together, results of the present study suggested that DLBS1033 is safe for long-term administration, with a caution at a high dose used during pregnancy, and can be used in combination with one of the antiplatelet drugs.

Prophylactic effect of egualen sodium, a stable azulene derivative, on gastrointestinal damage induced by ischemia/reperfusion, double antiplatelet therapy and loxoprofen in rats.

We examined the effect of egualen, a stable azulene derivative, against gastric damage induced by ischemia/reperfusion (I/R), gastric bleeding induced by double antiplatelet therapy with aspirin (ASA) plus clopidogrel, and small intestinal damage generated by loxoprofen, and investigated the possible mechanisms involved in its protective action. Male C57BL/6 mice or SD rats were used under urethane anesthesia (gastric lesions) or in a conscious (intestinal lesions) state. I/R-induced gastric injury was produced in mice by clamping the celiac artery for 30 min, followed by reperfusion for 60 min. Gastric bleeding was induced in rats by luminal perfusion with 25 mM ASA+50 mM HCl for 2 hours in the presence of clopidogrel (30 mg/kg). To produce small intestinal lesions the rats were given loxoprofen (60 mg/kg) p.o. and killed 24 hours later. Egualen was given i.d. 60 min before I/R or ASA perfusion, while given p.o. twice 30 min before and 6 hours after loxoprofen. Egualen significantly prevented the I/R-induced gastric damage, and the effect was equivalent to that of seratrodast (TXA2 antagonist). This agent also significantly suppressed gastric bleeding induced by ASA plus clopidogrel, similar to PGE2. Likewise, egualen significantly prevented loxoprofen-induced damage in the small intestine, accompanied by an increase in the secretion of mucus and suppression of bacterial invasion as well as iNOS expression. These results suggest that egualen has a prophylactic effect against various lesions in the gastrointestinal mucosa, probably through its characteristic pharmacological properties, such as TXA2 antagonistic action, local mucosal protection, and stimulation of mucus secretion.