Drug Metabolism Letters

BACKGROUND: Mass balance studies conducted using radiolabeled material (14C or 3H) definitively characterize the absorption, metabolism, and excretion (AME) of a drug. A critical aspect of these studies is that the radiotracer maintains its proportion to total drug from its administration to its complete elimination from the body. In the study of GDC-0276 in beagle dogs, we observed that the 14C radiotracer proportion (specific activity) varied through the study. METHOD: High resolution-accurate mass spectrometric measurements of 12C and 14C isotopes of GDC-0276 and its metabolites in plasma and excreta samples were used to determine the apparent specific activities, which were higher than the specific activity of the dosing formulation...

BACKGROUND: "Branched tail" oxyquinolines, and adaptaquin in particular, are potent HIF prolyl hydroxylase inhibitors showing promising results in in vivo hemorrhagic stroke models. The further improvement of the potency resulted in identification of a number of adaptaquin analogs. Early evaluation of toxicity and metabolism is desired right at the step of lead selection. OBJECTIVES: The aim of the study is to characterize the toxicity and metabolism of adaptaquin and its new improved analogs...

BACKGROUND: Bupropion (BUP) is widely used as an antidepressant and smoking cessation aid. There are three major pharmacologically active metabolites of BUP, erythrohydrobupropion (EB), hydroxybupropion (OHB) and threohydrobupropion (TB). At present, the mechanisms underlying the overall disposition and systemic clearance of BUP and its metabolites have not been well understood, and the role of transporters has not been studied. OBJECTIVE: The goal of this study was to investigate whether BUP and its active metabolites are substrates of the major hepatic uptake and efflux transporters...

Background The cocktail approach of probing drug metabolizing enzymes, in particular cytochrome P450 (CYP) enzymes, is a corner stone in clinical pharmacology studies. The first report of the famous "Pittsburg cocktail" has led the way for the availability of numerous cocktail substrate mixtures that provide options for indexing of CYP enzymes and/or evaluating the perpetrator capacity of the drug. Objectives The key objectives were: 1) to collate, tabulate, and discuss the various cocktail substrates to determine specific CYP enzyme activity in clinical pharmacology studies with specific case studies; 2) to introspect on how the cocktail approach has withstood the test of time and evolved for enabling key decision(s); 3) to provide some futuristic views on the use of cocktail in drug discovery and development...

The intake of complementary and alternative medicines leads to various drug interactions, which may affect pharmacodynamics or pharmacokinetics. This study was conducted to determine the interaction of glipizide (GZ) with an aqueous extract of Azadirachta indica (AZI) leaves. The pharmacokinetics and pharmacodynamics were evaluated through the oral glucose tolerance test, high Fat diet (HFD) and streptozotocin-induced diabetes in Wistar rats. In vitro CYP3A Activity of AZI at 50µg and 100 µg was assessed using liver microsomes...

BACKGROUND: Age has significant impact on activities of hepatic metabolizing enzymes in humans and animals. Flavin-containing monooxygenase (FMO) and aldehyde oxidase are two important hepatic enzymes. Understanding of impact of age on these two enzymes is still limited. This work was to investigate growth impact on hepatic FMO and AO activities in domestic male pigs. METHODS: Porcine liver microsomes and cytosol were prepared from the livers of male domestic pigs at ages of 1 day, 2, 5, 10 and 20 weeks...

Diclofenac is a non-steroidal antiinflammatory drug. It is predominantly metabolized by CYP2C9. 4̍-hydroxydiclofenac and its quinoneimine are the metabolites of diclofenac. However, few numbers of serious cases of idiosyncratic hepatotoxicity due to diclofenac metabolism were reported. The formation of the quinoneimine metabolite was found to be responsible for this idiosyncratic toxicity. Quinoneimine is an over-oxidized metabolite of diclofenac. In this work, computational studies were conducted to detail the formation of a quinoneimine metabolite from diclofenac...

We report here an evaluation of a novel experimental system- cofactor-supplemented permeabilized cryopreserved human enterocytes (MetMax™ cryopreserved human enterocytes (MMHE), patent pending) for applications in the evaluation of enteric drug metabolism. A major advantage of MMHE over conventional cryopreserved human enterocytes (CCHE) is the simplification of the use procedures including storage at -80o C instead of in liquid nitrogen, and use of the cells immediately after thawing without a need for centrifugation and microscopic evaluation of cell density and viability and cell density adjustment...

BACKGROUND: The use of poly-pharmacy in the present day clinical therapy has made identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP inhibition potential and/or the metabolic fate for such metabolites. OBJECTIVE: The key objectives were: a) to evaluate the in vitro CYP inhibition potential of select parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of parent drugs and metabolites...

BACKGROUND: There is a continued need for improvements in the efficiency of metabolite structure elucidation. OBJECTIVE: We propose to take LC retention time (RT) into consideration during the process of structure determination. METHOD: Herein we develop a simple methodology that employs a chromatographic hydrophobicity index (CHI) framework for standardizing LC conditions and introduce and utilize the concept of a predictable CHI change upon Phase 1 biotransformation (CHIbt)...

BACKGROUND: Few studies have systematically investigated pregnancy-induced changes in protein abundance of drug transporters in organs important for drug/xenobiotic disposition. OBJECTIVE: The goal of this study was to compare protein abundance of important drug/xenobiotic transporters including Abcb1a, Abcg2, Abcc2, and Slco1b2 in the liver, kidney and brain of pregnant mice on gestation day 15 to that of non-pregnant mice. METHODS: The mass spectrometry-based proteomics was used to quantify changes in protein abundance of transporters in tissues from pregnant and non-pregnant mice...

BACKGROUND: Acyl glucuronides of xenobiotics have been a subject of wide interest from the pharmaceutical industry with respect biochemical reactivity, hepatic disposition, and enterohepatic circulation. The reactivity and lack of stability of an acyl glucuronide for a clinical candidate could pose major developability concerns. To date, multiple in vitro assays have been published to assess the risk associated with acyl glucuronides. Despite this fact, the translation of these findings to predicting clinical safety remains poor...

BACKGROUND: The high levels of blood alcohol achieved with chronic plus binge alcohol exposures are somewhat reduced by co-administration of tobacco specific Nicotine-Derived Nitrosamine Ketone (NNK) suggesting that NNK may alter alcohol metabolism. OBJECTIVE: To test this hypothesis, we We examined ethanol and acetaldehyde-metabolizing enzyme activities and malondialdehyde adduct formation in rats exposed to ethanol (chronic + binge), NNK, or both. METHODS: 4-week old Long Evans rats were fed liquid diets containing 0% or 26% caloric ethanol for 8 weeks...

No abstract text is available yet for this article.

No abstract text is available yet for this article.

BACKGROUND: Genistein (5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is the most abundant isoflavone in soybean, which has been associated with a lower risk of development of cancer and cardiovascular diseases. Of particular interest regarding cancer preventive properties of flavonoids is their interaction with cytochrome P450 enzymes (CYPs). However, contradictory data report the effect of genistein on expression of СYPs enzymes. OBJECTIVE: The aim of this study was to investigate the effects of genistein on cytochrome P450 (CYP) gene expression levels in human hepatocellular carcinoma (HepG2/C3A) and colon adenocarcinoma (HT29) cells...

BACKGROUND: Nebivolol is a drug available as a racemate of d-nebivolol (SRRR) and lnebivolol (RSSS). In human liver microsomes, CYP2D6 mainly catalyses the metabolism of lnebivolol, while CYP2C19 catalyses the metabolism of d-nebivolol. Nebivolol stereoselective pharmacokinetics has been described only for extensive metabolizers (EM). OBJECTIVE: To describe the stereoseletive nebivolol pharmacokinetics in CYP2D6 poor metabolizers (PM) and to assess whether the phenotype has an impact on nebivolol pharmacokinetics...

BACKGROUND: Recently, it has been an increasing concern on the bioactivation and adverse reactions associated with consumption of herbal and nature products. 7-Ethoxycoumarin is one of coumarin family compounds, but little information is available regarding its potential reactive metabolites. METHOD: 7-ethoxylcoumarin was incubated individually with human, monkey, dog and rat hepatocytes for 2 hr, metabolites were detected, identified and characterized using high resolution liquid chromagraphy - tandem mass spectrometry...

BACKGROUND: The nonrenal clearance of drugs mediated by hepatic reduction is selectively altered by kidney disease. This study evaluated the influence of uremic serum on the expression and activity of reductase enzymes. METHODS: Human hepatocellular carcinoma cells (HepG2) were incubated with 5% pooled serum collected from patients with hemodialysis (pre- and post-dialysis session) or control subjects. The mRNA expression of various aldo-keto (AKR1C) and carbonyl (CBR) reductases were measured...

BACKGROUND & OBJECTIVE: Since the release of ivacaftor-lumacaftor, several red-flags have been raised that highlight the clinical efficacy of this combination strategy that may be limited due to antagonistic drug-drug interactions. METHOD: The effect of ivacaftor, its major metabolites M1 and M6, lumacaftor and the novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator tezacaftor at 10 µg/mL on the enzymatic activity of the major xenobiotic metabolizing enzymes CYP1A2 and CYP3A4 as well as the minor enzymes CYP2B6 and CYP2C9 was assayed...