No abstract

BACKGROUND AND PURPOSE Intracellular pharmacokinetics of anticancer drugs in multi‐drug resistance (MDR) cancer cells is hugely important in the evaluation and improvement of drug efficacy. By using adriamycin as a probe drug in MDR cancer cells, we developed a cellular pharmacokinetic‐pharmacodynamic (PK‐PD) model to reveal the correlation between cellular pharmacokinetic properties and drug resistance. In addition, the ability of 20(S)‐ginsenoside Rh2 (20(S)‐Rh2) to reverse MDR was further investigated. EXPERIMENTAL APPROACH The cellular pharmacokinetics of adriamycin were analysed visually and quantitatively in human breast cancer cells MCF‐7 and in adriamycin‐resistant MCF‐7 (MCF‐7/Adr) cells. Mitochondria membrane potential was assayed to evaluate the apoptotic effect of adriamycin. Subsequently, a PK‐PD model was developed via MATLAB. KEY RESULTS Visual and quantitative data of the dynamic subcellular distribution of adriamycin revealed that it accumulated in cells, especially nuclei, to a lesser and slower extent in MCF‐7/Adr than in MCF‐7 cells. 20(S)‐Rh2 increased the rate and amount of adriamycin entering cellular/subcellular compartments in MCF‐7/Adr cells through inhibition of P‐glycoprotein (P‐gp) activity, in turn augmenting adriamycin‐induced apoptosis. The integrated PK‐PD model mathematically revealed the pharmacokinetic mechanisms of adriamycin resistance in MCF‐7/Adr cells and its reversal by 20(S)‐Rh2. CONCLUSIONS AND IMPLICATIONS P‐gp, which is overexpressed and functionally active at cellular/subcellular membranes, influences the cellular pharmacokinetic and pharmacological properties of adriamycin in MCF‐7/Adr cells. Inhibition of P‐gp activity represents a key mechanism by which 20(S)‐Rh2 attenuates adriamycin resistance. Even more importantly, our findings provide a new strategy to explore the in‐depth mechanisms of MDR and evaluate the efficacy of MDR modulators.

ABSTRACT:The potential for herb-drug interactions has recently received greater attention worldwide, considering the fact that the use of herbal products becomes more and more widespread. The goal of this work was to examine the potential for the metabolism-based drug interaction arising from seven active components (danshensu, protocatechuic aldehyde, protocatechuic acid, salvianolic acid B, tanshinone I, tanshinone IIA, and cryptotanshinone) of danshen extract. Probe substrates of cytochrome P450 enzymes were incubated in human liver microsomes (HLMs) with or without each component of danshen extract. IC 50 and K i values were estimated, and the types of inhibition were determined. Among the seven components of danshen extract, tanshinone I, tanshinone IIA, and cryptotanshinone were potent competitive inhibitors of CYP1A2 (K i ‫؍‬ 0.48, 1.0, and 0.45 M, respectively); danshensu was a competitive inhibitor of CYP2C9 (K i ‫؍‬ 35 M), and cryptotanshinone was a moderate mixed-type inhibitor of CYP2C9 (K i ‫؍‬ 8 M); cryptotanshinone inhibited weakly and in mixed mode against CYP2D6 activity (K i ‫؍‬ 68 M), and tanshinone I was a weak inhibitor of CYP2D6 (IC 50 ‫؍‬ 120 M); and protocatechuic aldehyde was a weak inhibitor of CYP3A4 (IC 50 ‫؍‬ 130 and 160 M for midazolam and testosterone, respectively). These findings provided some useful information for safe and effective use of danshen preparations in clinical practice. Our data indicated that it was necessary to study the in vivo interactions between drugs and pharmaceuticals with danshen extract.

ABSTRACT:This study aimed to evaluate the effects of Schisandra lignan extract (SLE) with short-and long-term pretreatment on regulating rat hepatic and intestinal CYP3A for a comprehensive evaluation of metabolism-based herb-drug interactions. Inhibitory effects of SLE and its major components on rat CYP3A were confirmed in both hepatic and intestinal microsomal incubation systems. After a single dose of SLE pretreatment, higher C max and area under the concentration-time curves from zero to infinity (AUC 0-ؕ ) values were observed for intragastric midazolam (MDZ), whereas those for the intravenous MDZ were little changed. The mechanismbased inhibition of SLE toward CYP3A was further confirmed in vivo, characterized with a recovery half-life of 38 h. In contrast, SLE long-term treatment enhanced both hepatic (2.5-fold) and intestinal (4.0-fold) CYP3A protein expression and promoted the in vivo clearance of MDZ. When MDZ was coadministered with SLE after a consecutive long-term treatment, the AUC 0-ؕ value of MDZ was still lower than that of the control group, suggesting a much stronger inducing than inhibiting effect of SLE toward CYP3A. Furthermore, the intragastric administration of SLE exhibited a more intensive regulating effect toward intestinal than hepatic CYP3A, which could be partially explained by the relatively high exposures of lignans in the intestine. In conclusion, this study provides a comprehensive map for showing the complicated effects of SLE and its components on regulating rat CYP3A. The important findings are that SLE possesses a much stronger inducing than inhibiting effect on CYP3A, as well as a more intensive regulating effect on intestinal than hepatic CYP3A.

No abstract