Health News

Contributions of Arylacetamide Deacetylase and Carboxylesterase 2 to Flutamide Hydrolysis in Human Liver [Short Communications]

Flutamide, an antiandrogen drug, is widely used for the treatment of prostate cancer. The major metabolic pathways of flutamide are hydroxylation and hydrolysis. The hydrolyzed metabolite, 5-amino-2-nitrobenzotrifluoride (FLU-1), is further metabolized to N-hydroxy FLU-1, an assumed hepatotoxicant. Our previous study demonstrated that arylacetamide deacetylase (AADAC), one of the major serine esterases expressed in the human liver and gastrointestinal tract, catalyzes the flutamide hydrolysis. However, the enzyme kinetics in human tissue microsomes were not consistent with the kinetics by recombinant human AADAC. Thus, it seemed that AADAC is not the sole enzyme responsible for flutamide hydrolysis in human. In the present study, we found that recombinant carboxylesterase (CES) 2 could hydrolyze flutamide at low concentrations of flutamide. In the inhibition assay, the flutamide hydrolase activities at a flutamide concentration of 5 μM in human liver and jejunum microsomes were strongly inhibited by a selective CES2 inhibitor, 10 μM loperamide, with the residual activities of 22.9 ± 3.5 and 18.6 ± 0.7%, respectively. These results suggest that CES2 is also involved in the flutamide hydrolysis in human tissues. Using six individual human livers, the contributions of AADAC and CES2 to flutamide hydrolysis were estimated by using the relative activity factor. The relative contribution of CES2 was approximately 75 to 99% at the concentration of 5 μM flutamide. In contrast, the relative contribution of AADAC increased in parallel with the concentration of flutamide. Thus, CES2, rather than AADAC, largely contributed to the flutamide hydrolysis in clinical therapeutics.

Probiotics Reduce Antibiotic Diarrhea
Title: Probiotics Reduce Antibiotic Diarrheabr /Category: Health Newsbr /Created: 5/9/2012 11:01:00 AMbr /Last Editorial Review: 5/9/2012 12:00:00 AM

U.S. Bests Canada, Europe in Drug Approvals
Title: U.S. Bests Canada, Europe in Drug Approvalsbr /Category: Health Newsbr /Created: 5/16/2012 6:05:00 PMbr /Last Editorial Review: 5/17/2012 12:00:00 AM

Combined Contributions of Impaired Hepatic CYP2C11 and Intestinal Breast Cancer Resistance Protein Activities and Expression to Increased Oral Glibenclamide Exposure in Rats with Streptozotocin-Induced Diabetes Mellitus [Articles]

The purpose of this study was to evaluate the contributions of impaired cytochrome P450 and breast cancer resistance protein (BCRP) activity and expression to drug pharmacokinetics under diabetic conditions. Diabetes was induced in rats with the intraperitoneal administration of streptozocin. Glibenclamide (GLB), a substrate of BCRP, served as a model drug. The pharmacokinetics of orally administered GLB (10 mg/kg) were studied. The results showed that diabetes mellitus significantly increased exposure (area under the curve and peak concentration) to GLB after oral administration. Data from hepatic microsomes suggested impairment of GLB metabolism in diabetic rats. GLB metabolism in hepatic microsomes was significantly inhibited by a selective inhibitor (sulfaphenazole) of CYP2C11 and an anti-CYP2C11 antibody. Western blotting further indicated the contribution of impaired CYP2C11 expression to the impairment of GLB metabolism. Excretion data showed that ~72% of the orally administered dose was excreted in the feces of normal rats, which indicates an important role for intestinal BCRP. Diabetes significantly decreased the recovery from feces, which was only 40% of the orally administered dose. Results from in situ, single-pass, intestinal perfusion experiments revealed that diabetes significantly increased the apparent effective permeability and decreased the efflux of GLB through the intestine; this suggests impairment of intestinal BCRP function, which may play a role in the increased exposure to orally administered GLB in diabetic rats. Insulin treatment partly or completely reversed the changes in diabetic rats. All results yielded the conclusion that impaired hepatic CYP2C11 and intestinal BCRP expression and activity induced by diabetes contributed to the increased exposure of orally administered GLB.

Afghan Karzai: Thanks for ‘your taxpayers’ money’
pa href="http://news.yahoo.com/blogs/ticket/afghanistan-karzai-thanks-obama-taxpayers-money-182925141.html"img src="http://l1.yimg.com/bt/api/res/1.2/zOpTIaGqsR1XgM5uVOnFwA--/YXBwaWQ9eW5ld3M7Zmk9ZmlsbDtoPTg2O3E9ODU7dz0xMzA-/http://media.zenfs.com/en_us/News/Reuters/2012-05-20T171742Z_01_WHT304_RTRIDSP_3_NATO-SUMMIT.jpg" width="130" height="86" alt="U.S. President Obama shakes hands with Afghanistan President Karzai in Chicago" align="left" title="U.S. President Obama shakes hands with Afghanistan President Karzai in Chicago" border="0" //aLooking to a day when "the Afghan war as we understand it is over," President Barack Obama met Sunday with Afghan President Hamid Karzai to discuss NATO's withdrawal from that strife-torn country by the end of 2014. Obama, who has put the draw-down of combat troops at the heart of his foreign policy, declared that "the [...]/pbr clear="all"/

Many Who First Misuse Prescription Pills Get Them From Friends, Family: Report
Title: Many Who First Misuse Prescription Pills Get Them From Friends, Family: Reportbr /Category: Health Newsbr /Created: 4/25/2012 4:05:00 PMbr /Last Editorial Review: 4/26/2012 12:00:00 AM

Ablation of Both Organic Cation Transporter (Oct)1 and Oct2 Alters Metformin Pharmacokinetics but Has No Effect on Tissue Drug Exposure and Pharmacodynamics [Articles]

Organic cation transporter (OCT)1 and OCT2 mediate hepatic uptake and secretory renal clearance of metformin, respectively. Pharmacokinetic/pharmacodynamic (PK/PD) implications of simultaneous impairment of both transporters, such as by systemic pan-OCT inhibition, have not been studied directly. At present metformin PK/PD, distribution, and excretion were studied in Oct1/Oct2-knockout mice. Metformin clearance was reduced 4.5-fold from renal blood flow to unbound glomerular filtration rate, and volume of distribution was reduced 3.5-fold in Oct1/Oct2-knockout mice. Oral bioavailability was not affected (F = 64 ± 4 versus 59 ± 11; knockout versus wild type). Liver- and kidney-to-plasma concentration ratios were decreased in Oct1/Oct2-knockout mice 4.2- and 2.5-fold, respectively. The 2.9-fold increase in oral metformin exposure and reduced tissue partitioning yielded little to no net change in tissue drug concentrations. Absolute kidney exposure was unchanged (knockout/wild type = 1.1 ± 0.2), and liver exposure was only modestly decreased (knockout/wild type = 0.6 ± 0.1). Oral glucose area under the curve (AUC) lowering by metformin was not impaired in Oct1/Oct2-knockout mice at the five dose levels tested (ED₅₀ = 151 versus 110 mg/kg; glucose lowering at highest dose = 42 ± 1 versus 39 ± 4%; knockout versus wild type); however, higher systemic metformin exposures were necessary in knockout mice to elicit the same effect (half-maximal efficacious AUC = 70 versus 26 μg · h/ml). Despite major changes in metformin clearance and volume of distribution in Oct1/Oct2-knockout mice, tissue drug exposure and PD were not affected. These findings challenge the presumption that systemic OCT inhibition will affect metformin pharmacology.