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Drug Metabolism (drug + metabolism)
Terms modified by Drug Metabolism Selected AbstractsMichael D. Coleman Human Drug Metabolism: An Introduction Wiley, Chichester, 2005, 274 pp, Hardback Ł70.00, ISBN 0-470-86352-8JOURNAL OF APPLIED TOXICOLOGY, Issue 4 2006Philip W. Harvey No abstract is available for this article. [source] Poster Session 3 , Drug MetabolismJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue S1 2003Article first published online: 18 FEB 2010 No abstract is available for this article. [source] The Biochemistry of Drug Metabolism , An IntroductionCHEMISTRY & BIODIVERSITY, Issue 10 2009Abstract This review on intra-individual factors affecting drug metabolism completes our series on the biochemistry of drug metabolism. The article presents the molecular mechanisms causing intra-individual differences in enzyme expression and activity. They include enzyme induction by transcriptional activation and enzyme inhibition on the protein level. The influencing factors are of physiological, pathological, or external origin. Tissue characteristics and developmental age strongly influence enzyme-expression patterns. Further influencing factors are pregnancy, disease, or biological rhythms. Xenobiotics, drugs, constituents of herbal remedies, food constituents, ethanol, and tobacco can all influence enzyme expression or activity and, hence, affect drug metabolism. [source] The Biochemistry of Drug Metabolism , An IntroductionCHEMISTRY & BIODIVERSITY, Issue 7 2009Part 6. No abstract is available for this article. [source] The Biochemistry of Drug Metabolism , An IntroductionCHEMISTRY & BIODIVERSITY, Issue 5 2009Abstract This review continues a general presentation of the metabolism of drugs and other xenobiotics begun in five recent issues of Chemistry & Biodiversity. The present Part is dedicated to the pharmacological and toxicological consequences of drug and xenobiotic metabolism. In other words, the key concepts here are activation vs. deactivation, toxification vs. detoxification, and their interplay. These concepts are illustrated with a number of medicinally, toxicologically, and environmentally relevant examples. But, far from being concerned only with individual cases, the review is based on broad classifications, global rationalizations, and synthetic hypotheses. [source] The Biochemistry of Drug Metabolism , An IntroductionCHEMISTRY & BIODIVERSITY, Issue 12 2008Part 6. Abstract This review is part of a series of review articles on the metabolism of drugs and other xenobiotics published in Chemistry & Biodiversity. After a thorough discussion of metabolic reactions and their enzymes, this article focuses on genetically determined differences in drug and xenobiotic metabolism. After a short introduction on the causes for genetic differences, the first focus is on species differences in drug and xenobiotic metabolism. A major chapter is then dedicated to clinically relevant genetic polymorphisms in human drug metabolism and resultant ethnic differences. The last two chapters deal with sex-dependent differences in drug metabolism and personalized pharmacotherapy related to inter-individual differences in drug metabolism. [source] The Biochemistry of Drug Metabolism , An IntroductionCHEMISTRY & BIODIVERSITY, Issue 11 2008Abstract This review continues a general presentation of the metabolism of drugs and other xenobiotics begun in three recent issues of Chemistry & Biodiversity. The present Part is dedicated to reactions of conjugation, namely methylation, sulfonation, and phosphorylation, glucuronidation and other glycosidations, acetylation and other acylations, the formation and fate of coenzyme A conjugates, glutathione conjugation, and the reaction of amines with carbonyl compounds. It presents the many transferases involved, their nomenclature, relevant biochemical properties, catalytic mechanisms, and the reactions they catalyze. Nonenzymatic reactions, mainly of glutathione conjugation, also receive due attention. A number of medicinally, environmentally, and toxicologically relevant examples are presented and discussed. [source] The Biochemistry of Drug Metabolism , An IntroductionCHEMISTRY & BIODIVERSITY, Issue 3 2007Abstract This review continues a general presentation of the metabolism of drugs and other xenobiotics started in a recent issue of Chemistry & Biodiversity. This Part,2 presents the numerous oxidoreductases involved, their nomenclature, relevant biochemical properties, catalytic mechanisms, and the very diverse reactions they catalyze. Many medicinally, environmentally, and toxicologically relevant examples are presented and discussed. Cytochromes P450 occupy a majority of the pages of Part,2, but a large number of relevant oxidoreductases are also considered, e.g., flavin-containing monooxygenases, amine oxidases, molybdenum hydroxylases, peroxidases, and the innumerable dehydrogenases/reductases. [source] The Biochemistry of Drug Metabolism , An IntroductionCHEMISTRY & BIODIVERSITY, Issue 10 2006Abstract This paper reviews the general principles and concepts underlying Drug and Xenobiotic Metabolism. Its five Chapters deal with: 1.1. Drugs and Xenobiotics, 1.2. What are Drug Disposition and Metabolism?, 1.3. Where does Drug Metabolism Occur?, 1.4. Consequences of Drug Metabolism -- An Overview, and 1.5. Drug Metabolism and Drug Discovery. This review is the first of seven Parts which will be published at intervals. The subsequent Parts will cover: 2. Redox Reactions and Their Enzymes, 3. Reactions of Hydrolysis and Their Enzymes, 4. Conjugation Reactions and Their Enzymes, 5. Metabolism and Bioactivity, 6. Inter-Individual Factors Affecting Drug Metabolism, and 7. Intra-Individual Factors Affecting Drug Metabolism. [source] Drug metabolism and disposition in childrenFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2003M. Strolin Benedetti Abstract Key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the pediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, bacterial colonization and probably P-glycoprotein are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein concentration and plasma protein characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and probably P-glycoprotein, mainly that present in the gut, liver and brain. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I enzymes [oxidative (e.g. cytochrome CYP3A7 vs. CYP3A4 and CYP1A2), reductive and hydrolytic enzymes] and phase II enzymes (e.g. N -methyltransferases and glucuronosyltransferases). Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the pediatric population compared with adults are glomerular filtration and tubular secretion. It would be important to generate information on the developmental aspects of renal P-glycoprotein and of other renal transporters as done and still being done with the different isozymes involved in drug metabolism. [source] Drug metabolism and pharmacogenetics: the British contribution to fields of international significanceBRITISH JOURNAL OF PHARMACOLOGY, Issue S1 2006John Caldwell The branch of pharmacology we now call ,drug metabolism', the consideration of the enzymes and procesess determining the disposition of drugs in the body, emerged in the 1840s on the continent of Europe, but British science made little or no contribution until the 1920s. From this point on, the development of the field through the 20th century was shaped to a very significant extent by a series of influential British workers, whose contributions were of global significance and who can now be seen as fathers of the subject. Since the 1950s, and gaining pace inexorably from the 1970s, the significance of drug metabolism to human therapeutics has been greatly added to by the emergence of pharmacogenetics, clinically important hereditary variation in response to drugs, which underpins the current emphasis on personalised medicine. This review examines the British contributions to both these fields through the lives of seven key contributors and attempts to place their work both in the context of its time and its lasting influence. British Journal of Pharmacology (2006) 147, S89,S99. doi:10.1038/sj.bjp.0706466 [source] The use of in vitro technologies coupled with high resolution accurate mass LC-MS for studying drug metabolism in equine drug surveillanceDRUG TESTING AND ANALYSIS, Issue 1 2010James P. Scarth Abstract The detection of drug abuse in horseracing often requires knowledge of drug metabolism, especially if urine is the matrix of choice. In this study, equine liver/lung microsomes/S9 tissue fractions were used to study the phase I metabolism of eight drugs of relevance to equine drug surveillance (acepromazine, azaperone, celecoxib, fentanyl, fluphenazine, mepivacaine, methylphenidate and tripelennamine). In vitro samples were analyzed qualitatively alongside samples originating from in vivo administrations using LC-MS on a high resolution accurate mass Thermo Orbitrap Discovery instrument and by LC-MS/MS on an Applied Biosystems Sciex 5500 Q Trap. Using high resolution accurate mass full-scan analysis on the Orbitrap, the in vitro systems were found to generate at least the two most abundant phase I metabolites observed in vitro for all eight drugs studied. In the majority of cases, in vitro experiments were also able to generate the minor in vivo metabolites and sometimes metabolites that were only observed in vitro. More detailed analyses of fentanyl incubates using LC-MS/MS showed that it was possible to generate good quality spectra from the metabolites generated in vitro. These data support the suggestion of using in vitro incubates as metabolite reference material in place of in vivo post-administration samples in accordance with new qualitative identification guidelines in the 2009 International Laboratory Accreditation Cooperation-G7 (ILAC-G7) document. In summary, the in vitro and in vivo phase I metabolism results reported herein compare well and demonstrate the potential of in vitro studies to compliment, refine and reduce the existing equine in vivo paradigm. Copyright © 2010 John Wiley & Sons, Ltd. [source] The clinical impact of pharmacogenetics on the treatment of epilepsyEPILEPSIA, Issue 1 2009Wolfgang Löscher Summary Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA-B*1502, are at a higher risk for Stevens-Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy. [source] A Comparative Pharmacokinetic Study in Healthy Volunteers of the Effect of Carbamazepine and Oxcarbazepine on Cyp3a4EPILEPSIA, Issue 3 2007Astrid-Helene Andreasen Summary:,Purpose: Carbamazepine (CBZ) and oxcarbazepine (OXCZ) are well-known inducers of drug metabolism via CYP3A4. Indirect interaction studies and clinical experience suggest that CBZ has a stronger potential in this regard than OXCZ. However this has never been subject to a direct comparative study. We performed a study in healthy volunteers to investigate the relative inductive effect of CBZ and OXCZ on CYP3A4 activity using the metabolism of quinidine as a biomarker reaction. Methods: Ten healthy, male volunteers participated in an open, randomized crossover study consisting of two periods separated by a 4-week wash-out period. The subjects received 1200 mg oral OXCZ daily for 17 days and 800 mg oral CBZ for 17 days. A single 200 mg oral dose of quinidine was administered at baseline and following administration of CBZ and OXCZ. Outcome parameters were the formation clearance of 3-hydroxyquinidine dose and the ratio of the AUCs of 3-hydroxyquinidine to quinidine. Results: Formation clearance of 3-hydroxyquinidine was increased by means of 89% (CI: 36,164; p = 0.0022) and 181% (CI: 120,260, p < 0.0001) after treatment with OXCZ and CBZ, respectively, compared to baseline. The relative inductive effect of CBZ was 46% higher than for OXCZ. AUC ratio increased by means of 161% (CI: 139,187, p < 0.0001) (OXCZ) and 222% (CI: 192,257, p < 0.0001) (CBZ). Quinidine Cmax decreased by means of 29% (CI: 16,40, p = 0.0018) (OXCZ) and 33% (CI: 18,45, p = 0.0020) (CBZ). T˝ decreased by means of 12% (CI: 6,17, p < 0.0014) (OXCZ) and 32% (CI: 25,38, p < 0.0001) (CBZ). tmax was not changed in either period. Conclusion: We confirm a clinically significant inductive effect of both OXCZ and CBZ. The inductive effect of CBZ was about 46% higher than that of OXCZ, a difference that may be of clinical relevance. [source] Variable expression of CYP and Pgp genes in the human small intestineEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2003M. Lindell Abstract Background ,The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome P450 and P-Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes. Methods ,The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT-PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed. Results ,Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively. Conclusions ,Extensive interindividual variability is characteristic for the expression of drug-metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation. [source] Impact of inter-individual differences in drug metabolism and pharmacokinetics on safety evaluationFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2004J.L.C.M. Dorne Abstract Safety evaluation aims to assess the dose,response relationship to determine a dose/level of exposure for food contaminants below which no deleterious effect is measurable that is ,without appreciable health risk' when consumed daily over a lifetime. These safe levels, such as the acceptable daily intake (ADI) have been derived from animal studies using surrogates for the threshold such as the no-observed-adverse-effect-level (NOAEL). The extrapolation from the NOAEL to the human safe intake uses a 100-fold uncertainty factor, defined as the product of two 10-fold factors allowing for human variability and interspecies differences. The 10-fold factor for human variability has been further subdivided into two factors of 100.5 (3.16) to cover toxicokinetics and toxicodynamics and this subdivsion allows for the replacement of an uncertainty factor with a chemical-specific adjustment factor (CSAF) when compound-specific data are available. Recently, an analysis of human variability in pharmacokinetics for phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferase, glucuronidation, glycine conjugation, sulphation) and renal excretion was used to derive pathway-related uncertainty factors in subgroups of the human population (healthy adults, effects of ethnicity and age). Overall, the pathway-related uncertainty factors (99th centile) were above the toxicokinetic uncertainty factor for healthy adults exposed to xenobiotics handled by polymorphic metabolic pathways (and assuming the parent compound was the proximate toxicant) such as CYP2D6 poor metabolizers (26), CYP2C19 poor metabolizers (52) and NAT-2 slow acetylators (5.2). Neonates were the most susceptible subgroup of the population for pathways with available data [CYP1A2 and glucuronidation (12), CYP3A4 (14), glycine conjugation (28)]. Data for polymorphic pathways were not available in neonates but uncertainty factors of up to 45 and 9 would allow for the variability observed in children for CYP2D6 and CYP2C19 metabolism, respectively. This review presents an overview on the history of uncertainty factors, the main conclusions drawn from the analysis of inter-individual differences in metabolism and pharmacokinetics, the development of pathway-related uncertainty factors and their use in chemical risk assessment. [source] Drug metabolism and disposition in childrenFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2003M. Strolin Benedetti Abstract Key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the pediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, bacterial colonization and probably P-glycoprotein are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein concentration and plasma protein characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and probably P-glycoprotein, mainly that present in the gut, liver and brain. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I enzymes [oxidative (e.g. cytochrome CYP3A7 vs. CYP3A4 and CYP1A2), reductive and hydrolytic enzymes] and phase II enzymes (e.g. N -methyltransferases and glucuronosyltransferases). Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the pediatric population compared with adults are glomerular filtration and tubular secretion. It would be important to generate information on the developmental aspects of renal P-glycoprotein and of other renal transporters as done and still being done with the different isozymes involved in drug metabolism. [source] In vivo metabolic effects of naringenin in the ethanol consuming rat and the effect of naringenin on adipocytes in vitroJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 3-4 2007K. Szkudelska Summary Naringenin is a bioactive flavanone involved in the inhibition of drug metabolism which exhibits antioxidant, anti-inflammatory and anticancerogenic properties and which recently appeared to be a factor mitigating the hyperlipidaemic effects in rats and rabbits. In the performed experiment, the effect of naringenin, administered intragastrically (50 mg/kg) for 2 weeks to normal and ethanol drinking rats, on insulin and leptin levels and on some metabolic parameters was investigated. Naringenin did not change the hormone levels in any group of rats. Blood glucose, triglyceride, total, esterified and free cholesterol and high-density lipoprotein-cholesterol concentrations were also unaffected by this compound. Only free fatty acids were elevated after the naringenin treatment in the water-drinking rats. In spite of unchanged glucose and insulin concentrations in blood, the tested flavanone reduced the glucose/insulin ratio in ethanol-receiving rats. Liver triglycerides, elevated due to ethanol ingestion, were partially normalized by naringenin. Other tested parameters like liver glycogen and cholesterol, muscle triglycerides and glycogen were not altered in any group of rats. The influence of naringenin (62.5, 125, 250 and 500 ,m) on basal and insulin-stimulated glucose conversion to lipids (lipogenesis) as well as on basal and epinephrine-stimulated glycerol release (lipolysis) in the isolated rat adipocytes was also tested. The basal and the stimulated lipogenesis tended to be decreased in the presence of the flavanone (250 ,m). This inhibitory effect intensified and was statistically significant at the highest concentration of naringenin. The tested compound did not evoke any effect on basal lipolysis while the epinephrine-stimulated process was limited at the highest concentration of the flavanone. Naringenin (62.5, 125, 250 and 500 ,m) had no effect on leptin secretion from the isolated rat adipocytes. Results obtained in our studies demonstrate that naringenin exerts a very weak influence on carbohydrate and lipid metabolism of normal and ethanol-consuming rats and on metabolism of isolated rat adipocytes. [source] Gender divergent expression of Nqo1 in Sprague Dawley and August Copenhagen x Irish ratsJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 2 2008Lisa M. Augustine In the mammalian liver, there is an abundance of enzymes that function to enable the safe and efficient elimination of potentially harmful xenobiotics that are encountered through environmental exposure. A variety of factors, including gender and genetic polymorphisms, contribute to the variation between an individual system's detoxification capacity and thus its ability to protect itself against oxidative stress, cellular damage, cell death, etc. NAD(P)H:quinone oxidoreducatase 1 (Nqo1) is an antioxidant enzyme that plays a major role in reducing reactive electrophiles, thereby protecting cells from free-radical damage and oxidative stress. The goal of this study was to determine the gender-specific expression and inducibility of Nqo1 in the Sprague Dawley (SD) and August Copenhagen x Irish (ACI) rat strains, two strains that are commonly used in drug metabolism and drug-induced enzyme induction, toxicity, and carcinogenesis studies. Nqo1 mRNA, protein, and activity levels were determined through 96 h in SD and ACI males and females following treatment with known Nqo1 inducers oltipraz and butylated hydroxyanisole. In the SD strain, gender dimorphic expression of Nqo1 was observed with female mRNA, protein, and activity levels being significantly higher than in males. In contrast, there were minimal differences in Nqo1 mRNA, protein, and activity levels between ACI males and females. The gender dimorphic expression of Nqo1 in the SD rats was maintained through the course of induction, with female-induced levels greater than male-induced levels indicating that SD females may have a greater capacity to protect against oxidative stress and thus a decreased susceptibility to carcinogens. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:93,100, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20224 [source] CYP3A4 and pregnane X receptor humanized miceJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 4 2007Frank J. Gonzalez Abstract Marked species differences exist in P450 expression and activities. In order to produce mouse models that can be used to more accurately predict human drug and carcinogen metabolism, P450- and xenobiotic receptor humanized mice are being prepared using bacterial artificial chromosomes (BAC) and P1 phage artificial chromosomes (PAC) genomic clones. In some cases, transgenic mice carrying the human genes are bred with null-mice to produce fully humanized mice. Mice expressing human CYP1A1, CYP1A2, CYP2E1, CYP2D6, CYP3A4, and CYP3A7 were generated and characterized. Studies with the CYP3A4-humanized (hCYP3A4) mouse line revealed new information on the physiological function of this P450 and its role in drug metabolism in vivo. With this mouse line, CYP3A4, under certain circumstances, was found to alter the serum levels of estrogen resulting in deficient lactation and low pup survival as a result of underdeveloped mammary glands. This hCYP3A4 mouse established the importance of intestinal CYP3A4 in the pharmacokinetics of orally administered drugs. The hCYP3A4 mice were also used to establish the mechanisms of potential gender differences in CYP3A4 expression (adult female > adult male) that could account for human gender differences in drug metabolism and response. The pregnane X receptor (PXR) is also involved in induction of drug metabolism through its target genes including CYP3A4. Since species differences exist in ligand specificity between human and mice, a PXR -humanized mouse (hPXR) was produced that responds to human PXR activators such as rifampicin but does not respond to the rodent activator pregnenalone 16,-carbonitrile. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:158,162, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20173 [source] Labelling of the guanylate cyclase activator cinaciguat (BAY 58-2667) with carbon-14, tritium and stable isotopesJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 3 2010D. Seidel Abstract For studies of pharmacokinetics and drug metabolism of the new soluble guanylate cyclase activator cinaciguat (BAY 58-2667) the 14C-labelled compound was synthesized. The tritiated compound was required to elucidate the mode of action and the stable labelled compound was required for bio-analytical studies by quantitative mass spectrometry as well. Two radiosyntheses are described with different formation of the labelled intermediate 1-(chloro[14C]methyl)-4-(2-phenylethyl)benzene. The first one started with 14C-carboxylation of 1-bromo-4-(2-phenylethyl)benzene yielding the desired product in 5 steps. In the second synthesis intermediate 1-(chloro[14C]methyl)-4-(2-phenylethyl)benzene was formed by chloromethylation of bibenzyl with [14C]paraformaldehyde/hydrochloric acid subsequently resulting in the final product in three steps. Tritium labelling was performed by tritium exchange of the diester intermediate using an organo-iridium catalyst and subsequent saponification. The stable labelled compound was synthesized via a convergent synthesis starting with 13C,15N-cyanation of 1-(chloromethyl)-2-{[4-(2-phenylethyl)benzyl]oxy}benzene and 13C-cyanation of methyl 4-bromobenzoate, respectively. The labelled product was obtained after 7 chemical steps. Copyright © 2010 John Wiley & Sons, Ltd. [source] An efficient synthesis of [13C6]-3,5-dichloroanilineJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 7 2008Bachir Latli Abstract 3,5-Dichloroaniline is commonly found in many compounds with pharmacological and other biological activities. [13C6]-Aniline or its hydrochloride salt was converted in three steps to [13C6]-3,5-dichloroaniline, which can be incorporated in compounds of interest and used as internal standards in drug metabolism and pharmacokinetics (DMPK) studies. Copyright © 2008 John Wiley & Sons, Ltd. [source] Synthesis of [14C]-labelled vardenafil hydrochloride and metabolitesJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 11 2003D. Seidel Abstract For studies of pharmacokinetics and drug metabolism of the new orally active, selective phosphodiesterase type V (PDE V) inhibitor vardenafil (Levitra®), the 14C-labelled version was synthesised. Starting from the cyanation of 2-iodophenol with K14CN, an 8-step synthesis led to two batches with 0.727 g (2.857 GBq) and 2.199 g (5.497 GBq) of [triazinone- 14C]vardenafil hydrochlo-ride with different specific radioactivities. The label was located in position 2 of the imidazotriazinone moiety. Several carbon-14 labelled metabolites were synthesised as reference compounds for metabolism studies. Copyright © 2003 John Wiley & Sons, Ltd. [source] Synthesis of 14C-labeled E4010JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 12 2001N. Watanabe Abstract 14C-Labeled E4010, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy) -piperidino]-6-[4- 14C]phthalazinecarbonitrile monohydrochloride was synthesized for drug metabolism and pharmacokinetic studies using [1-chloro-4-(3-chloro-4-methoxybenzyl)amino]-6-[4- 14C]phthalazinecarbonitrile as the starting material. The radiochemical yield was 33.4%. The specific radioactivity and radiochemical purity, as determined by radio-HPLC and LSC, were 4.77 MBq/mg and 99.8%, respectively. Copyright © 2001 John Wiley & Sons, Ltd. [source] Rapid screening and characterization of drug metabolites using a new quadrupole,linear ion trap mass spectrometerJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 2 2003Gérard Hopfgartner Abstract The application of a new hybrid RF/DC quadrupole,linear ion trap mass spectrometer to support drug metabolism and pharmacokinetic studies is described. The instrument is based on a quadrupole ion path and is capable of conventional tandem mass spectrometry (MS/MS) as well as several high-sensitivity ion trap MS scans using the final quadrupole as a linear ion trap. Several pharmaceutical compounds, including trocade, remikiren and tolcapone, were used to evaluate the capabilities of the system with positive and negative turbo ionspray, using either information-dependent data acquisition (IDA) or targeted analysis for the screening, identification and quantification of metabolites. Owing to the MS/MS in-space configuration, quadrupole-like CID spectra with ion trap sensitivity can be obtained without the classical low mass cutoff of 3D ion traps. The system also has MS3 capability which allows fragmentation cascades to be followed. The combination of constant neutral loss or precursor ion scan with the enhanced product ion scan was found to be very selective for identifying metabolites at the picogram level in very complex matrices. Owing to the very high cycle time and, depending on the mass range, up to eight different MS experiments could be performed simultaneously without compromising chromatographic performance. Targeted product ion analysis was found to be complementary to IDA, in particular for very low concentrations. Comparable sensitivity was found in enhanced product ion scan and selected reaction monitoring modes. The instrument is particularly suitable for both qualitative and quantitative analysis. Copyright © 2003 John Wiley & Sons, Ltd. [source] Modulation of hepatic cytochrome P450 during Listeria monocytogenes infection of the brainJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2003Elena Garcia Del Busto Cano Abstract Hepatic cytochrome P450 enzymes can be modulated during systemic infections. Inflammatory responses in the brain have also been shown to cause a significant decrease in the levels and activities of important cytochrome P450 isoforms in the liver. We determined some of the effects of central nervous system (CNS) Listeria monocytogenes infection on hepatic cytochrome P450 systems in rats. Intracerebroventricular injection of L. monocytogenes resulted in a time-dependent modulation of CYP1A, CYP2B, and CYP3A activities in the liver. Total hepatic cytochrome P450 content was significantly lowered 48 h after administration of the bacterium, and hepatic CYP1A and CYP2B activities were significantly altered 48 and 72 h after infection, respectively, whereas CYP3A activity and protein content were depressed 72 h after the insult. Bacterial load in the brain increased dramatically over a 72-h period, but the number of bacteria cultured from liver over this time period was relatively small. Therefore, an infection largely confined to the CNS in the rat results in abnormal activity levels of certain hepatic cytochrome P450 enzymes crucial in drug metabolism. If such a response also occurs in humans, this has the potential to produce serious complications with drug and endogenous substrate metabolism in patients with an infectious disease involving the CNS. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1860,1868, 2003 [source] Stereospecific reduction of the original anticancer drug oracin in rat extrahepatic tissuesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2003Barbora Szotáková ABSTRACT The liver is the major site of drug metabolism in the body. However, many drugs undergo metabolism in extrahepatic sites and in the gut wall and lumen. In this study, the distribution and activity of reductases in rat that reduced potential cytostatic oracin to its principal metabolite 11-dihydrooracin (DHO) were investigated. The extension and stereospecificity of oracin reduction to DHO were tested in microsomal and cytosolic fractions from the liver, kidney, heart, lung and wall of small intestine, caecum and large intestine. Intestinal bacterial reduction of oracin was studied as well. The amount of DHO enantiomers was measured by HPLC with Chiralcel OD-R as chiral column. Reductive biotransformation of oracin was mostly stereospecific for (+)-DHO, but the enantiomeric ratio differed significantly among individual tissues and subcellular fractions (from 56% (+)-DHO in heart microsomes to 92% (+)-DHO in liver cytosol). Stereospecificity for (-)-DHO (60%) was observed in bacterial oracin reduction in the lumen of small intestine, caecum and large intestine. Shift of the (+)-DHO/(-)-DHO enantiomeric ratio from 90:10 (in liver subcellular fractions) to 60:40 (in-vivo) clearly demonstrated the importance of the contribution of extrahepatic metabolism to the total biotransformation of oracin to DHO. [source] Analysis of 4-methyl-piperazine-1-carbodithioic acid 3-cyano-3,3-diphenyl-propyl ester hydrochloride and its major metabolites in rat plasma and tissues by LC-MS/MSJOURNAL OF SEPARATION SCIENCE, JSS, Issue 13 2007Xiaomei Jiang Abstract 4-Methyl-piperazine-1-carbodithioic acid 3-cyano-3,3-diphenylpropyl ester hydrochloride (TM-208) is a newly synthesized compound, which has shown excellent in vivo and in vitro anticancer activity and low toxicity. To investigate the metabolism of TM-208 in rats, in the present study, we administered TM-208 orally to rats and analyzed its metabolites existing in rat plasma and central tissues by LC-MS/MS. Rat plasma and tissue samples were collected before or after a single oral dose (250 mg/kg) of TM-208, then the analytes were extracted from samples by liquid,liquid extraction and analyzed using LC-MS/MS. The structures of proposed metabolites were elucidated according to the rules of drug metabolism and disposition in vivo and the characteristic fragmentation behaviors of TM-208 in ESI-ITMSn. Five metabolites (M1,M5) were tentatively or assuredly identified: (2-amino-ethyl)-dithiocarbamic acid 3-cyano-3,3-diphenyl-propyl ester (M1), (2-methylamino-ethyl)-dithiocarbamic acid 3-cyano-3,3-diphenyl-propyl ester (M2), 4-methyl-piperazine-1-carbothioic acid S -(3-cyano-3,3-diphenyl-propyl) ester (M3), piperazine-1-carbodithioic acid 3-cyano-3,3-diphenylpropyl ester (M4), and sulfine of (4-methyl-piperazine-1-carbodithioic acid 3-cyano-3,3-diphenylpropyl ester) (M5). [source] The Coxib NSAIDs: Potential Clinical and Pharmacologic Importance in Veterinary MedicineJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2005Mary Sarah Bergh Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to control acute and chronic pain as well as to manage oncologic and neurologic diseases in human and veterinary patients. Despite ongoing research and efforts to improve the safety and efficacy of existing drugs, adverse effects such as gastrointestinal irritation, renal and hepatic toxicity, interference with hemostasis, and reproductive problems persist. The true incidence of NSAID-induced adverse effects in animals is unknown, but is likely underestimated, because cats and dogs may be more sensitive than humans to NSAIDs due to alterations in drug metabolism, absorption, and enterohepatic recirculation. NSAIDs produce both analgesia and toxic adverse effects primarily by inhibiting cyclooxygenase (COX), thereby decreasing the production of prostaglandins that signal inflammation and pain as well as mediate physiologic functions such as platelet aggregation, gastric protection, and electrolyte balance in the kidney. The presence of at least 2 COX isoforms may account for variability in NSAID efficacy and toxicity both within and among species. This paper reviews and evaluates the published literature on the safety, pharmacology, uses, and complications of a subclass of COX-1,sparing drugs, the coxibs, in veterinary medicine. Coxibs and other COX-1,sparing drugs provide a clinically useful improvement over traditional NSAIDs, but data are incomplete and more in vivo species-specific, target-tissue, and clinical studies are needed. [source] Porphyrin distribution after topical aminolevulinic acid in a novel porcine model of sebaceous skin,,LASERS IN SURGERY AND MEDICINE, Issue 2 2009Fernanda H. Sakamoto MD Abstract Background and Objective Aminolevulinic acid photodynamic therapy (ALA-PDT) depends on drug metabolism into porphyrins. Clinically, ALA-PDT has been used with a wide range of protocols for treating both epidermal and dermal targets, despite limited understanding of porphyrin biodistribution over time. We studied porphyrin accumulation after topical application of ALA in vivo, and also describe the porcine ear as a new animal model to study adnexal glands. Study Design/Materials and Methods The microanatomy of anterior ear skin of swine was measured. Topical 20% ALA in water/ethanol was applied under occlusion. Biopsies taken after 5, 10, 15, and then every 15 minutes for a total of 3 hours were examined by fluorescence microscopy of frozen sections to assess accumulation and distribution of porphyrins. Results Porphyrin fluorescence of digital photomicrograph images was not visually apparent until 30,45 minutes after application, although quantitative pixel analysis showed a statistically significant increase in epidermal fluorescence only 15 minutes after ALA application. From 30 to 120 minutes, epidermis, hair follicles (HF), and sebaceous glands (SG) became progressively more fluorescent. Eccrine gland fluorescence began to be detected after 30 minutes; SG showed fluorescence starting at 45,75 minutes. Fluorescence in all sites reached maximum intensity from 75 to 180 minutes of incubation. There was a trend for HF and SG to express stronger fluorescence compared with epidermis and eccrine glands. Conclusion Anterior pig ear skin is microanatomically similar to human sebaceous skin. The time-dependent accumulation of porphyrins in pilosebaceous units and eccrine glands in this model suggests other routes of uptake of topical ALA in addition to the trans-epidermal route. Apparently, time interval between ALA application and light exposure could be optimized for different uses of ALA-PDT. Lasers Surg. Med. 41:154,160, 2009. © 2009 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||