Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimer's disease, across the blood-brain barrier.
Cryptotanshinone (CTS), a major constituent from the roots of Salvia miltiorrhiza (Danshen), is widely used in the treatment of coronary heart disease, stroke and less commonly Alzheimer's disease. Our recent study indicates that CTS is a substrate for P-glycoprotein (PgP/MDR1/ABCB1). This study has investigated the nature of the brain distribution of CTS across the brain-blood barrier (BBB) using several in vitro and in vivo rodent models. A polarized transport of CTS was found in rat primary microvascular endothelial cell (RBMVEC) monolayers, with facilitated efflux from the abluminal side to luminal side. Addition of a PgP (e.g. verapamil and quinidine) or multi-drug resistance protein 1/2 (MRP1/2) inhibitor (e.g. probenecid and MK-571) in both luminal and abluminal sides attenuated the polarized transport. In a bilateral in situ brain perfusion model, the uptake of CTS into the cerebrum increased from 0.52 +/- 0.1% at 1 min to 11.13 +/- 2.36 ml/100 g tissue at 30 min and was significantly greater than that of sucrose. Co-perfusion of a PgP/MDR1 (e.g. verapamil) or MRP1/2 inhibitor (e.g. probenecid) significantly increased the brain distribution of CTS by 35.1-163.6%. The brain levels of CTS were only about 21% of those in plasma, and were significantly increased when coadministered with verapamil or probenecid in rats. The brain levels of CTS in rats subjected to middle cerebral artery occlusion and rats treated with quinolinic acid (a neurotoxin) were about 2- to 2.5-fold higher than the control rats. Moreover, the brain levels in mdr1a(-/-) and mrp1(-/-) mice were 10.9- and 1.5-fold higher than those in the wild-type mice, respectively. Taken collectively, these findings indicate that PgP and Mrp1 limit the brain penetration of CTS in rodents, suggesting a possible role of PgP and MRP1 in limiting the brain penetration of CTS in patients and causing drug resistance to Danshen therapy and interactions with conventional drugs that are substrates of PgP and MRP1. Further studies are needed to explore the role of other drug transporters in restricting the brain penetration of CTS and the clinical relevance.
Yu
Xi-Yong
XY
Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Provincial Cardiovascular Institute, Guangzhou 510080, China.
Lin
Shu-Guang
SG
Chen
Xiao
X
Zhou
Zhi-Wei
ZW
Liang
Jun
J
Duan
Wei
W
Chowbay
Balram
B
Wen
Jing-Yuan
JY
Chan
Eli
E
Cao
Jie
J
Li
Chun-Guang
CG
Zhou
Shu-Feng
SF
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002199:Capillary Permeability; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000627:therapeutic use; D042783:Endothelial Cells / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D010616:Phenanthrenes / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018517:Plant Roots; D017378:Quinolinic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D027561:Salvia miltiorrhiza / Q000737:chemistry; D020521:Stroke / Q000188:drug therapy; D014018:Tissue Distribution; D014315:Triterpenes / Q000493:pharmacokinetics
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D004365:Drugs, Chinese Herbal; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018696:Neuroprotective Agents; D010616:Phenanthrenes; D017378:Quinolinic Acid; D014315:Triterpenes; C037886:cryptotanshinone; C095122:multidrug resistance protein 3; C421109:multidrug resistance-associated protein 1