title: Effects of salvianolic acid B and tanshinone IIA on the pharmacokinetics of losartan in rats by regulating the activities and expression of CYP3A4 and CYP2C9.
abstract: Losartan (LST) is a common chemical drug used to treat high blood pressure and reduce the risk of stroke in certain people with heart disease. Danshen, prepared from the dried root and rhizome of Salvia miltiorrhiza Bunge, has been widely used for prevention and treatment of various cardiovascular and cerebrovascular diseases. There are more than 35 formulations containing Danshen indexed in the 2010 Chinese Pharmacopoeia, which are often combined with LST to treat cardiovascular and cerebrovascular diseases in the clinic. The effects of the two major components of Danshen, salvianolic acid B (SA-B) and tanshinone IIA (Tan IIA), on the pharmacokinetics of losartan and its metabolite, EXP3174, in rats were investigated by liquid chromatography coupled with mass spectrometry (LC-MS). Male Sprague-Dawley rats were randomly assigned to 3 groups: LST, LST+SA-B and LST+Tan IIA, and the main pharmacokinetic parameters were estimated after oral administration of LST, LST+SA-B and LST+Tan IIA. It was found that there are significant differences in the pharmacokinetic parameters among the three groups: Cmax, t1/2, AUC, AUMC in the LST+SA-B group was smaller than those in group LST, while larger in group LST+Tan IIA. Further, the effects of SA-B and Tan IIA on the metabolism of losartan was also investigated using rat liver microsomes in vitro. The results indicated that SA-B can induce the metabolism of LST, while Tan IIA can inhibit the metabolism of LST in rat liver microsomes in vitro by regulating activities of CYP450 enzymes. In addition, the effect of SA-B and Tan IIA on CYP3A4 and CYP2C9 expression was studied in Chang liver cells by western-blotting and Real-time PCR. It was concluded that the two components of Danshen, SA-B and Tan IIA have different influences on the metabolism of LST: SA-B can obviously speed up the metabolism of LST by inducing CYP3A4/CYP2C9 activities and expression, however, Tan IIA can slow down the metabolism of LST by inhibiting CYP3A4/CYP2C9 activities.
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mo He Rd, Shanghai 201999, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mo He Rd, Shanghai 201999, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mo He Rd, Shanghai 201999, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mo He Rd, Shanghai 201999, China. Electronic address: nmxyyf@126.com.
authors.forename: Yongfang
authors.initials: Y
authors.lastname: Yuan
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics*; D001572:Benzofurans / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D019808:Losartan / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D053630:Depsides
chemical_list: D045784:Abietanes; D000959:Antihypertensive Agents; D001572:Benzofurans; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D004365:Drugs, Chinese Herbal; D019808:Losartan; D012333:RNA, Messenger; C021751:tanshinone; C076944:salvianolic acid B; D053630:Depsides; C450260:CYP2C9 protein, human; C465260:Cyp3a2 protein, rat; C066026:losartan carboxylic acid
keywords: Cytochrome P450; Drug metabolism; Losartan; Salvia miltiorrhiza Bunge; Salvianolic acid B; Tanshinone IIA