Drug Metabolism Letters - Volume 2, Issue 3, 2008

It is my great pleasure to introduce Drug Metabolism Letters (DML; www.bentham.org/dml) to the Readers as a unique journal in the field, which has gained recognition among its audience within a very brief span of time since its launch back in January 2007. The journal has already been accepted for coverage in Chemical Abstracts, EMBASE, EMBiology and Scopus! DML publishes short papers/letters on major advances in Read More

We used immortalized human hepatocytes to study the bioactivation of leflunomide and the metabolic degradation to its major metabolic,A77 1726. Both leflunomide and A77 1726 caused a time-and concentration-dependent increase in LDH release. The cytotoxicity of leflunomide,but not that of A77 1726, was prevented by the pan -CYP inhibitor, 1-aminobenzotriazole,indicating that an oxidative metabolite(s) was responsi Read More

Rat liver microsomes attached to nanoparticles were used for LC-MS studies of CYP3A and 2E1 enzymes in metabolism of N -nitro so compounds.Using these biocolloids,turnover rates were measured within 2 min. Inhibitor IC 50 values for ketoconazole(KET) and 4-methylpyrazoie (4-MEP) were estimated.

Cyclosporin A (CsA) is a P-glycoprotein (P-gp) inhibitor clinically used as an immunosuppressant. Itraconazole (ITZ) functions as an inhibitor of both the P-gp and CYP3A and is used as afungistatic/fungicidal agent in human and veterinary medicine. The present studies were designed to investigate the effects of CsA and ITZ on 1 intestinal permeability of amlodipine (a calcium channel blocker used as a cardiovascular age Read More

The SXR humanized mouse modle was used to quantitatively assess an vivo induction response of the human PXR agoinst, rifampicin, Three days of rifampicin treatment increased RNA expression and microsomel enzyme activity of CYP3A, as wall as significantly reduced triazolam plasma exposure. These results indicate that the humanized SXR mouse can be used as a modle to prediict human CYP3A4 induction and the re Read More

Aldehyde oxidase (AO) is a cytosolic enzyme that contributes to the Phase I metabolism of xenobiotics in human and preclinical species. We compared AO activity in cytosol and cryopreserved hepatocytes from human, monkey, rat and mouse livers to assess species differences. We also evaluated possible species differences in drug interactions using seven drugs known to inhibit human cytosolic AO i.e. raloxifene, perphe Read More

I do hope the DML Reader will find all twelve papers included in this issue, to be quite interesting: Urs A. Boelsterli et al.. studied the bioactivation of leflunomide and the metabolic degradation to its major metabolite, A771726. Leflunomide was rapidly metabolized in human hepatocytes to A771726, but its toxicity was dependent on other, CYP-dependent intermediates. James F. Rusling and colleagues used rat liver microso Read More

The influence of the enzyme source such as phospholipid and expression ratio of NADPHcytochrome P450 reductase on midazolam 1'-hydroxylation activity of cytochrome P450 3A4 was investigated in reconstituted systems and in membranes using bicistronic expressions. Preferable ratio of P450 reductase over human P450 3A4 would be a determinant factor for the drug metabolism studies.

The great emphasis on ethical and humane treatment of animals in biomedical research has culminated in the promulgation of the rule of 3Rs - Replacement, Reduction, and Refinement. We have proposed an addition to the 3Rs - a fourth R for Recycling the animal. In drug discovery single-dose pharmacokinetic studies in rats, each animal is generally used only once and then euthanized. A reduction in the number of rats us Read More

We used protein-ligand docking and minimization to identify celecoxib as an allosteric modulator of SULT2A1-catalyzed estradiol sulfonation. Subsequent to celecoxib docking and complex minimization, conformational changes in SULT2A1 allowed estradiol docking to an alternative binding region with predicted preference for 17β-OH-E2 sulfonation over 3-OH-E2 sulfonation.

A fast and sensitive method was developed for the assessment of CYP induction in human hepatocytes cultured in 96-well plates. The effects on CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 were examined by means of mass spectrometry and the well-known cocktail strategy. The performance of the method was tested by using prototypic inducers such as methylcolanthrene, phenobarbital and rifampicin. The Read More

UGT enzymes catalyze the formation of glucuronic acid conjugates. Specifically selected representative stable isotope (C13, N15) labeled peptide internal standards of each enzyme were employed to quantify UGTs 1A1 and 1A6 by LC-MS/MS using isotope dilution techniques. Inter-day variability (n=5) for human liver microsomes was ≤ 8.0 % for UGT1A1 and ≤ 19 % for UGT1A6. Comparison within a human liver micros Read More

The extracts from the root of Salvia miltiorrhiza are widely used in the treatment of angina and stroke. In this study, we have investigated the role of P-glycoprotein (P-gp) in the transport of tanshinone I (TSI), a major active constituent of S. miltiorrhiza. The TSI transport across Caco-2 monolayers was pH-, energy-, and temperature-dependent, but not sodium-dependent. TSI exhibited a polarized transport in Caco-2 mo Read More