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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

A Mechanistic Study of the Intestinal Absorption of Cryptotanshinone, the Major Active Constituent of Salvia miltiorrhiza

Departments of Pharmacy (J.Z., S.Y.C., S.Z.) and Biological Sciences (Y.-H.H.), Faculty of Science, and Departments of Biochemistry (W.D., H.-Y.Y.) and Pharmacology (J.-S.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; and Institute of Clinical Pharmacology, School of Pharmaceutical Sciences (M.H., S.G., H.-C.B., Y.P.) and Department of Pharmacy (X.C.), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China

The nature of intestinal absorption of most herbal medicine is unknown. Cryptotanshinone (CTS) is the principal active constituent of the widely used cardiovascular herb Salvia miltiorrhiza (Danshen). We investigated the oral bioavailability of CTS in rats and the mechanism for its intestinal absorption using several in vitro and in vivo models: 1) Caco-2 cell monolayers; 2) monolayers of MDCKII cells overexpressing P-glycoprotein (PgP); and 3) single-pass rat intestinal perfusion with mesenteric vein cannulation. The systemic bioavailabilities of CTS after oral and intraperitoneal administration at 100 mg/kg were 2.05 and 10.60%, respectively. In the perfused rat intestinal model, permeability coefficients based on CTS disappearance from the luminal perfusate (P_lumen) were 6.7- to 10.3-fold higher than permeability coefficients based on drug appearance in venous blood (P_blood). P_blood significantly increased in the presence of the P-gP inhibitor, verapamil. CTS transport across Caco-2 monolayers was pH-, temperature- and ATP-dependent. The transport from the apical (AP) to the basolateral (BL) side was 3- to 9-fold lower than that from the BL to the AP side. Inclusion of verapamil (50 µM) in both AP and BL sides abolished the polarized CTS transport across Caco-2 cells. Moreover, CTS was significantly more permeable in the BL to AP than in the AP to BL direction in MDCKII and MDR1-MDCKII cells. The permeability coefficients in the BL to AP direction were significantly higher in MDCKII cells overexpressing PgP. These findings indicate that CTS is a substrate for PgP that can pump CTS into the luminal side.

Address correspondence to: Dr. Shufeng Zhou, Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543. E-mail: phazsf{at}nus.edu.sg

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