Title: Over-the-Counter Products
Created: 12/12/1999 8:25:00 PM
Last Editorial Review: 11/18/2013 12:00:00 AM
Simultaneous Quantification of the Abundance of Several Cytochrome P450 and Uridine 5'-Diphospho-Glucuronosyltransferase Enzymes in Human Liver Microsomes Using Multiplexed Targeted Proteomics [Articles]
Cytochrome P450 (P450) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes mediate a major proportion of phase I and phase II metabolism of xenobiotics. In vitro-in vivo extrapolation (IVIVE) of hepatic clearance in conjunction with physiologically-based pharmacokinetics (PBPK) has become common practice in drug development. However, prediction of xenobiotic kinetics in virtual populations requires knowledge of both enzyme abundances and the extent to which these correlate. A multiplexed quantification concatemer (QconCAT) strategy was used in this study to quantify the expression of several P450 and UGT enzymes simultaneously and to establish correlations between various enzyme abundances in 24 individual liver samples (ages 27–66, 14 male). Abundances were comparable to previously reported values, including CYP2C9 (40.0 ± 26.0 pmol mg–1), CYP2D6 (11.9 ± 13.2 pmol mg–1), CYP3A4 (68.1 ± 52.3 pmol mg–1), UGT1A1 (33.6 ± 34.0 pmol mg–1), and UGT2B7 (82.9 ± 36.1 pmol mg–1), expressed as mean ± S.D. Previous reports of correlations in expression of various P450 (CYP3A4/CYP3A5*1/*3, CYP2C8/CYP2C9, and CYP3A4/CYP2B6) were confirmed. New correlations were demonstrated between UGTs [including UGT1A6/UGT1A9 (rs = 0.82, P < 0.0001) and UGT2B4/UGT2B15 (rs = 0.71, P < 0.0001)]. Expression of some P450 and UGT enzymes were shown to be correlated [including CYP1A2/UGT2B4 (rs = 0.67, P = 0.0002)]. The expression of CYP3A5 in individuals with *1/*3 genotype (n = 11) was higher than those with *3/*3 genotype (n = 10) (P < 0.0001). No significant effect of gender or history of smoking or alcohol use on enzyme expression was observed; however, expression of several enzymes declined with age. The correlation matrix produced for the first time by this study can be used to generate more realistic virtual populations with respect to abundance of various enzymes.
General to admit guilt on 3 counts; denies assault
RALEIGH, N.C. (AP) — A U.S. Army general accused of sexual assault was set to plead guilty to three lesser charges Thursday in a move that his lawyer says will strengthen his position going into trial.
Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy? [Special Section on Transporters in Toxicity and Disease]
P-glycoprotein (P-gp) is a key player in the multidrug-resistant phenotype in cancer. The protein confers resistance by mediating the ATP-dependent efflux of an astonishing array of anticancer drugs. Its broad specificity has been the subject of numerous attempts to inhibit the protein and restore the efficacy of anticancer drugs. The general strategy has been to develop compounds that either compete with anticancer drugs for transport or act as direct inhibitors of P-gp. Despite considerable in vitro success, there are no compounds currently available to "block" P-gp–mediated resistance in the clinic. The failure may be attributed to toxicity, adverse drug interaction, and numerous pharmacokinetic issues. This review provides a description of several alternative approaches to overcome the activity of P-gp in drug-resistant cells. These include 1) drugs that specifically target resistant cells, 2) novel nanotechnologies to provide high-dose, targeted delivery of anticancer drugs, 3) compounds that interfere with nongenomic transfer of resistance, and 4) approaches to reduce the expression of P-gp within tumors. Such approaches have been developed through the pursuit of greater understanding of resistance mediators such as P-gp, and they show considerable potential for further application.
Despite the name calling, Putin is not crazy
The Russian president may be calculating, sources say, even miscalculating.
Army's top sex crimes prosecutor faces groping allegation
The US Army's top prosecutor overseeing sexual assault cases has been suspended over allegations he groped a female lawyer working for him and tried to kiss her, officers said Thursday. The suspension of Lieutenant Colonel Joseph Morse marks the latest embarrassing setback for the US military as it battles a sexual assault crisis that has sparked calls for a radical overhaul of its judicial system. No charges have been filed against Morse, who supervises the army's special victim prosecutors that handle sexual assault, domestic abuse and crimes against children cases. The alleged incident took place in 2011 in a hotel room at a sexual assault legal conference in Alexandria, Virginia, officials said, before Morse was named to his current job.