Effect of pitavastatin in different SLCO1B1 backgrounds on repaglinide pharmacokinetics and pharmacodynamics in healthy Chinese males

The effect of pitavastatin and SLCO1B1 genetic background on the pharmacokinetic and pharmacodynamic properties of repaglinide was investigated. In this randomized, placebo-controlled, crossover study, twelve healthy Chinese males were administered with pitavastatin 4 mg/d or the placebo for 5 d followed by repaglinide 4 mg given orally on d 5. Plasma repaglinide and glucose levels were measured by liquid chromatography-tandem mass spectrometry [LC/MS/MS] and the glucose oxidase method, respectively. Treatment with pitavastatin significantly increased the peak plasma concentration [C[max]] of repaglinide [P=0.003] in SLCO1B1[asterisk]1b homozygotes [P=0.015] and SLCO1B1[asterisk]15 carriers [P=0.031]. Treatment with pitavastatin led to a marginal increase in the area under plasma concentration-time curve from 0 h to infinity [AUC[0][rightwards arrow][infinity]] of repaglinide [P=0.091]. There was no significant difference in pharmacokinetic parameters or hypoglycemic effects of repaglinide among SLCO1B1 genotypes in either the pitavastatin or control group. Pitavastatin increased the C[max] of the plasma concentration of repaglinide in an SLCO1B1 genotype dependent manner, but had no apparent effect on the pharmacodynamics of repaglinide in healthy volunteers. The p values for this statement were not reported

Induction of apoptosis in osteogenic sarcoma cells by combination of tumor necrosis factor-related apoptosis inducing ligand and chemotherapeutic agents / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Osteosarcoma is one of the most common primary malignant tumors of bone with poor prognosis. TNF-related apoptosis inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) cytokine family. TRAIL induces apoptosis in various tumor cell lines but is not found to be cytotoxic to many normal cell types in vitro. We investigated the cytotoxic activity of TRAIL and chemotherapeutic agents, including methotrexate (MTX), doxorubicin (DOX) and cisplatin (CDDP), on established osteosarcoma cell line--S-732.</p><p><b>METHODS</b>OS-732 cells were incubated with chemotherapeutic agents MTX, DOX and CDDP at various peak plasma concentrations (PPC), 0.1PPC, 1PPC and 10PPC, alone or with 100 ng/ml of TRAIL for 24 hours or 48 hours. MTT was used to evaluate the cytotoxic activity of different agents on OS-732. The apoptosis proportion was assayed by flow cytometry. Cellular morphologic changes were observed by phase contrast microscope, scan electron microscope, and transmission electron microscope.</p><p><b>RESULTS</b>The inhibitory rate was (24.438 +/- 3.414)% with TRAIL of 100 ng/ml for 24 hours. The cells were responsive to DOX and CDDP with a dose-effect relationship (P < 0.05). In OS-732 cells, DOX and CDDP cooperated synergistically with TRAIL when incubated the cells with them for 24 hours (the combined inhibitory rate is (58.360 +/- 2.146)% and (54.101 +/- 2.721)%, respectively). TRAIL alone or drugs alone induced the apoptosis rate was less than 25% (P < 0.05). However, the combination of TRAIL and MTX did not present synergistic effects on OS-732 cells (P > 0.05, compared with TRAIL alone).</p><p><b>CONCLUSIONS</b>Osteosarcoma OS-732 cells were not responsive to TRAIL-induced apoptosis. DOX and CDDP sensitize osteosarcoma OS-732 cells to TRAIL-induced apoptosis. The combination of TRAIL and MTX presented no synergistic effects on killing OS-732 cells.</p>