Micromolar concentrations of estradiol are required to inhibit the oxidation of low-density lipoproteins (LDL) in vitro. Recent evidence suggests that estradiol must be modified before it can become an effective antioxidant at physiological levels. Our aim was to determine other possible conditions under which low concentrations of 17b-estradiol can reduce LDL oxidation. LDL susceptibility to oxidation was monitored by measurements of conjugated diene formation. High levels of 17b-estradiol reduced oxidative modification of LDL. Vitamin C and vitamin E also increased LDL resistance to Cu21-mediated oxidation. More importantly, 10 nM 17b-estradiol, which on its own had no effect, exhibited significant antioxidant actions in the presence of either vitamins C or E. In conclusion, supraphysiological concentrations of 17b-estradiol are required to exert antioxidant effects directly in vitro. However, in the presence of vitamins C and E, concentrations of 17b-estradiol close to physiological levels can also protect LDL from oxidation.

Background: The glutathione S-transferase (GST) superfamily comprises multiple isozymes with compelling evidence of functional polymorphisms in various ethnic groups. All these mutations, in particular those in class A, k and u GST, are likely to contribute to interindividual differences in responses to xenobiotics including response to chemotherapy and associated with altered disease. The frequency of common GST mutations in Uygur Chinese is unknown. We investigated the common mutations of GSTM1, GSTT1, and GSTP1 in Uygur (N =154) Chinese and compare with Han Chinese (N =196). Method: GSTM1 and GSTT1 polymorphisms were analyzed by multiplexed PCR, and GSTP1 polymorphism was detected by PCR-based restriction fragment length polymorphism (RFLP) analysis. Results: GSTM1 null genotype was found in 53.2% Uygur Chinese, which was close to that in Han Chinese (56.1%) ( P=0.592). A significantly lower frequency ( P <0.05) of GSTT1 null genotype in Uygur Chinese (26.6%) was observed compared with Han Chinese (50.0%). Uygur Chinese exhibited a GSTP1 genotype distribution of 51.3% I/I, 40.2% I/V and 8.4% V/V, which was different from that in Han Chinese (60.7% I/I, 35.2% I/V and 4.1% V/V). Conclusions: There is marked ethnic difference in the frequency of common GSTT1 and GSTP1 mutation, but not GSTM1 mutation, between Uygur and Han Chinese. D 2005 Elsevier B.V. All rights reserved.

In vitro and in vivo studies have indicated that the induction or inhibition of cytochrome P450 (CYP) is one of the major mechanisms for some clinically important pharmacokinetic herb-drug interactions. An attempt was made to simulate the effects of herbal preparation with single or multiple CYP-inhibiting constituents on the area of the plasma concentration-time curve (AUC) of coadministered drug that was either a low clearance drug by intravenous (i.v.) injection or a high clearance drug by oral route. Our simulation studies indicated that the expected increase (Rc) in the AUC of the coadministered drug by inhibiting herbal constituent(s) was dependent on the route of administration. For low clearance drug by i.v. injection, Rc was generally determined by inhibition constant (Ki), unbound inhibitor concentration ([I]), hepatic fraction (fh), number of inhibitory herbal constituents (n) and metabolic pathway fraction in hepatic metabolism (fm), while Rc for a high clearance drug by oral route, Rc was determined by Ki, [I], n and fm. By varying these parameters, Rc changed accordingly. It appeared likely to predict a herb-drug metabolic interaction, if the inhibiting herbal constituents could be quantitatively determined. However, many herb- and drug-related factors may cause difficulties with the prediction, and thus in vivo animal and human studies are always necessary. Copyright

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated to determine the concentrations of adefovir [9-(2-phosphonylmethoxyethyl)adenine, PMEA] in human plasma. After one-step protein precipitation of plasma samples by methanol, adefovir was analyzed by LC/MS/MS using positive electrospray ionization. Chromatography was performed on a C18 column. The extraction recoveries of adefovir were found to be 85.1-89.3%. Adefovir was stable under routine laboratory conditions. A minimal matrix effect resulting in a slight ionization enhancement of adefovir (<10.9%) was observed, which did not markedly affect the behavior of the calibrations curves and accuracy and precision data. The method had a chromatographic run time of 7.8min and a linear calibration curve over the concentration range 1.5-90ng/mL for adefovir. The lower limit of quantification of the method was 1.5ng/mL. The intra-and inter-day precision was less than 8.4%. These results indicated that this LC/MS/MS method has high selectivity and efficiency, and acceptable accuracy, precision and sensitivity. The validated LC/MS/MS method has been successfully used in a pharmacokinetic study in healthy volunteers treated with oral adefovir dipivoxil at 10 and 20mg.