Effect of silymarin supplement on the pharmacokinetics of rosuvastatin.
OBJECTIVE
To evaluate the effect of silymarin on the pharmacokinetics of rosuvastatin in systems overexpressing OATP1B1 or BCRP transporters and in healthy subjects.


METHODS
The concentration-dependent transport of rosuvastatin and the inhibitory effect of silymarin were examined in vitro in OATP1B1-expressing oocytes and MDCKII-BCRP cells. For in vivo assessment, eight healthy male volunteers, divided into two groups, were randomly assigned to receive placebo or silymarin (140 mg) three times per day for 5 days. On day 4, all subjects received rosuvastatin (10 mg, 8 AM: ) 1 h after the placebo or silymarin administration. A series of blood samples were collected for 72 h, and the plasma concentration of rosuvastatin was determined using LC-MS/MS.


RESULTS
Based on the concentration dependency of rosuvastatin transport in the OATP1B1 and BCRP overexpression systems, rosuvastatin is a substrate for both transporters. Silymarin inhibited both OATP1B1- and BCRP-mediated rosuvastatin transport in vitro (K (i) 0.93 microM and 97 microM, respectively). However, no significant changes in AUC, half-life, Vd/F, or Cl/F of rosuvastatin were observed in human subjects following pretreatment with silymarin.


CONCLUSIONS
Silymarin does not appear to affect rosuvastatin pharmacokinetics in vivo, suggesting that silymarin, administered according to a recommended supplementation regimen, is not a potent modulator of OATP1B1 or BCRP in vivo.
Deng
Jian Wei
JW
Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, 633-165 Gaegum-Dong, Jin-Gu, Busan, 614-735, South Korea.
Shon
Ji-Hong
JH
Shin
Ho-Jung
HJ
Park
Soo-Jin
SJ
Yeo
Chang-Woo
CW
Zhou
Hong-Hao
HH
Song
Im-Sook
IS
Shin
Jae-Gook
JG
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000328:Adult; D000465:Algorithms; D000975:Antioxidants / Q000494:pharmacology*; D019540:Area Under Curve; D001693:Biological Transport, Active / Q000187:drug effects; D045744:Cell Line, Tumor; D018592:Cross-Over Studies; D019587:Dietary Supplements / Q000009:adverse effects*; D004347:Drug Interactions; D005260:Female; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D011743:Pyrimidines / Q000493:pharmacokinetics*; D000068718:Rosuvastatin Calcium; D012838:Silymarin / Q000494:pharmacology*; D013449:Sulfonamides / Q000493:pharmacokinetics*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000975:Antioxidants; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D011743:Pyrimidines; C503999:SLCO1B1 protein, human; D012838:Silymarin; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium