Determination of myocardium to plasma concentration ratios of five antipsychotic drugs: comparison with their ability to induce arrhythmia and sudden death in clinical practice.


:Reviewing available data shows that most of antipsychotic drugs are associated with arrhythmia and sudden death. Experimental studies have shown a HERG channel blockade, a dose-dependent increase in duration of action potential or of QT interval, with various degrees of indicators of serious arrhythmogenicity. However, it seems difficult to relate these in vitro and in vivo preclinical models to clinical findings, in part, because the relationship between concentrations used and in vivo tissue concentrations during treatment in man is not known. Consequently, we established the myocardium to plasma concentration ratios for a series of antipsychotic drugs by intraperitoneal administration of different level doses to the guinea pig. Then, we compared these values to their ability to induce arrhythmia or torsade de pointes in clinical practice. The myocardium to plasma concentration ratios were 2.2 for clozapine, 2.7 for olanzapine, 3.1 for sertindole, 4.5 for risperidone, and 6.4 for haloperidol. These data suggest that when the ratio is higher than 4, arrhythmia and sudden death may be expected. On the contrary, when the ratio is less than 3, little effect may be predicted. These results underscore the importance of interpreting HERG channel data and electrophysiological data in the context of other pharmacokinetic parameters such as myocardium to plasma distribution.


Toxicol Appl Pharmacol


Titier K,Canal M,Déridet E,Abouelfath A,Gromb S,Molimard M,Moore N




Has Abstract


2004-08-15 00:00:00














  • Predicting the oral uptake efficiency of chemicals in mammals: combining the hydrophilic and lipophilic range.

    abstract::Environmental risk assessment requires models for estimating the bioaccumulation of untested compounds. So far, bioaccumulation models have focused on lipophilic compounds, and only a few have included hydrophilic compounds. Our aim was to extend an existing bioaccumulation model to estimate the oral uptake efficiency...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: O'Connor IA,Huijbregts MA,Ragas AM,Hendriks AJ

    更新日期:2013-01-01 00:00:00

  • An animal model for the study of chronopharmacokinetics of drugs and application to methotrexate and vinorelbine.

    abstract::An animal model was designed to study the chronopharmacokinetics of intravenous drugs and applied to anticancer agents vinorelbine (VNB) and methotrexate (MTX). Each experiment was performed on four pigs housed in a standardized light-dark cycle (12:12). Four pigs received a 0.16-mg bolus of VNB, followed by a 60-h co...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Prémaud A,Rousseau A,Gicquel M,Ragot S,Manceau J,Laurentie M,Marquet P

    更新日期:2002-09-15 00:00:00

  • Lymphocyte beta2-adrenergic receptors and plasma catecholamine levels in lead-exposed workers.

    abstract::The effect of lead exposure on beta2-adrenoceptor density and catecholamine response was studied in 26 male workers and 1 female worker, exposed to lead on average for 6 years. The systolic blood pressure in lead workers (101-160 mmHg, 124.4 +/- 14.7 mmHg) was found to be significantly higher than in controls (97-134 ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Chang HR,Chen SS,Chen TJ,Ho CH,Chiang HC,Yu HS

    更新日期:1996-07-01 00:00:00

  • Testing of metoclopramide and procainamide for their ability to induce genotoxic effects in cultured mammalian cells.

    abstract::Metoclopramide (MCA) and procainamide (PCA), two widely used benzamide drugs developed before the present regulatory climate but recently found to induce DNA breaks in human lymphocytes, were evaluated for their genotoxic effects in cultured rodent and human cells. In subtoxic concentrations neither MCA (from 0.10 to ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Martelli A,Campart GB,Canonero R,Mattioli F,Brambilla G

    更新日期:1995-04-01 00:00:00

  • Ferritin and in vivo beryllium toxicity.

    abstract::Beryllium (Be+2), a divalent metal ion, is toxic to both man and animal. Although the molecular basis for its toxicity is unknown, it is well established that micromolar concentrations of beryllium specifically inhibit certain enzymes. Previous in vitro studies have shown that the presence of ferritin, an iron-storage...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Lindenschmidt RC,Sendelbach LE,Witschi HP,Price DJ,Fleming J,Joshi JG

    更新日期:1986-02-01 00:00:00

  • Inhibition of lymphocyte activation in splenic and gut-associated lymphoid tissues following oral exposure of mice to 7,12-dimethylbenz[a]anthracene.

    abstract::The hypothesis that 7,12-dimethyl-benz[a]anthracene (DMBA) suppresses immune function in mice via an inhibition of lymphocyte activation was examined in these studies. Daily exposure of B6C3F1 mice to DMBA (cumulative doses of 1.4 to 140 mg/kg) via the oral route for 14 days was found to inhibit phytohemagglutinin (PH...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Burchiel SW,Davis DA,Gomez MP,Montano RM,Barton SL,Seamer LC

    更新日期:1990-09-15 00:00:00

  • The enhanced value of combining conventional and "omics" analyses in early assessment of drug-induced hepatobiliary injury.

    abstract::The InnoMed PredTox consortium was formed to evaluate whether conventional preclinical safety assessment can be significantly enhanced by incorporation of molecular profiling ("omics") technologies. In short-term toxicological studies in rats, transcriptomics, proteomics and metabolomics data were collected and analyz...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Ellinger-Ziegelbauer H,Adler M,Amberg A,Brandenburg A,Callanan JJ,Connor S,Fountoulakis M,Gmuender H,Gruhler A,Hewitt P,Hodson M,Matheis KA,McCarthy D,Raschke M,Riefke B,Schmitt CS,Sieber M,Sposny A,Suter L,Sweatman

    更新日期:2011-04-15 00:00:00

  • Positron emission tomography in the quantification of cellular and biochemical responses to intrapulmonary particulates.

    abstract::Inhaled mineral dusts and fibres can cause chronic pulmonary inflammation, often leading to permanent scarring with loss of function, but the mechanisms involved remain obscure. There are currently no good methods for monitoring inflammatory processes in situ. Positron emission tomography (PET) of suitable intravenous...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章,评审


    authors: Jones HA,Hamacher K,Clark JC,Schofield JB,Krausz T,Haslett C,Boobis AR

    更新日期:2005-09-01 00:00:00

  • Localization of mercury in CNS of the rat. IV. The effect of selenium on orally administered organic and inorganic mercury.

    abstract::The distribution and exact cellular localization of mercury in the brain and upper cervical spinal cord of the adult male Wistar rat has been determined using the autometallographic silver-enhancement technique. A detailed atlas of mercury-containing nuclei following oral administration of HgCl2 (20 mg x liter-1 or CH...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Møller-Madsen B,Danscher G

    更新日期:1991-05-01 00:00:00

  • Effect of lycopene and beta-carotene on peroxynitrite-mediated cellular modifications.

    abstract::Peroxynitrite formed by the reaction of superoxide and nitric oxide is a highly reactive species with a role in various pathological processes such as cancer, chronic inflammation, and cardiovascular and neurological diseases. In the present study, the effect of the carotenoids, lycopene and beta-carotene, on peroxyni...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Muzandu K,Ishizuka M,Sakamoto KQ,Shaban Z,El Bohi K,Kazusaka A,Fujita S

    更新日期:2006-09-15 00:00:00

  • Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury.

    abstract::Exposure to excessive manganese (Mn) levels leads to neurotoxicity, referred to as manganism, which resembles Parkinson's disease (PD). Manganism is caused by neuronal injury in both cortical and subcortical regions, particularly in the basal ganglia. The basis for the selective neurotoxicity of Mn is not yet fully un...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Milatovic D,Gupta RC,Yu Y,Zaja-Milatovic S,Aschner M

    更新日期:2011-11-01 00:00:00

  • Induction of metallothionein by steroids in rat primary hepatocyte cultures.

    abstract::The purpose of this study was to characterize the induction of metallothionein (MT) by steroids in rat primary hepatocyte cultures. Comparison of the characteristics of MT induction by a steroid (dexamethasone) to that by metals (Zn and Cd), examination of the involvement of the glucocorticoid receptor in the steroid ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Bracken WM,Klaassen CD

    更新日期:1987-03-15 00:00:00

  • Distribution, teratogenicity, and embryonic delivered dose of retinoid Ro 23-9223.

    abstract::Ro 23-9223 is a highly lipophilic aromatic retinoid with antiproliferative and sebum supressive effects in preclinical disease models of acne. To investigate the relation between Ro 23-9223 developmental toxicity, drug distribution, and transplacental transfer, groups of pregnant hamsters were given oral doses of 50-5...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Willhite CC,Lovey A,Eckhoff C

    更新日期:2000-04-15 00:00:00

  • Combining an in silico proarrhythmic risk assay with a tPKPD model to predict QTc interval prolongation in the anesthetized guinea pig assay.

    abstract::Human-based in silico models are emerging as important tools to study the effects of integrating inward and outward ion channel currents to predict clinical proarrhythmic risk. The aims of this study were 2-fold: 1) Evaluate the capacity of an in silico model to predict QTc interval prolongation in the in vivo anesthe...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Morissette P,Polak S,Chain A,Zhai J,Imredy JP,Wildey MJ,Travis J,Fitzgerald K,Fanelli P,Passini E,Rodriguez B,Sannajust F,Regan C

    更新日期:2020-03-01 00:00:00

  • HBCDD-induced sustained reduction in mitochondrial membrane potential, ATP and steroidogenesis in peripubertal rat Leydig cells.

    abstract::Hexabromocyclododecane (HBCDD), a brominated flame retardant added to various consumer products, is a ubiquitous environmental contaminant. We have previously shown that 6-hour exposure to HBCDD disturbs basal and human chorionic gonadotropin (hCG)-induced steroidogenesis in rat Leydig cells. Reduction in mitochondria...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Fa S,Pogrmic-Majkic K,Samardzija D,Hrubik J,Glisic B,Kovacevic R,Andric N

    更新日期:2015-01-01 00:00:00

  • JBP485 improves gentamicin-induced acute renal failure by regulating the expression and function of Oat1 and Oat3 in rats.

    abstract::We investigated the effects of JBP485 (an anti-inflammatory dipeptide and a substrate of OAT) on regulation of the expression and function of renal Oat1 and Oat3, which can accelerate the excretion of accumulated uremic toxins (e.g. indoxyl sulfate) in the kidney to improve gentamicin-induced ARF in rats. JBP485 cause...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Guo X,Meng Q,Liu Q,Wang C,Sun H,Peng J,Ma X,Kaku T,Liu K

    更新日期:2013-09-01 00:00:00

  • Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line.

    abstract::Colon cancer is the third most incident type of cancer worldwide. One of the most important risk factors for colon cancer development are inflammatory bowel diseases (IBD), thus therapies focusing on IBD treatment have great potential to be used in cancer prevention. Nature has been a source of new therapeutic and pre...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Vendramini-Costa DB,Alcaide A,Pelizzaro-Rocha KJ,Talero E,Ávila-Román J,Garcia-Mauriño S,Pilli RA,de Carvalho JE,Motilva V

    更新日期:2016-06-01 00:00:00

  • Carcinogenicity of formaldehyde and hydrogen chloride in rats.

    abstract::Previous studies in this laboratory have shown that the combined exposure of hydrogen chloride (HCI) and formaldehyde vapors (HCHO) elicited a significant incidence of nasal cancer in rats. In studies performed elsewhere, it has been demonstrated that exposure to formaldehyde alone induced a high nasal cancer response...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Sellakumar AR,Snyder CA,Solomon JJ,Albert RE

    更新日期:1985-12-01 00:00:00

  • A plasticizer released from IV drip chambers elevates calcium levels in neurosecretory terminals.

    abstract::We report that intracellular calcium levels rise in mammalian neurosecretory terminals and in cultured pheochromocytoma cells during acute exposure to physiological medium incubated in IV drip chambers. The agent responsible for this effect is shown to be di(2-ethylhexyl)phthalate (DEHP). DEHP (800 nM) added to saline...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Tully K,Kupfer D,Dopico AM,Treistman SN

    更新日期:2000-11-01 00:00:00

  • Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease.

    abstract::Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) in epidemiologic studies. The purpose of this study was to evaluate the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Wahlang B,Song M,Beier JI,Cameron Falkner K,Al-Eryani L,Clair HB,Prough RA,Osborne TS,Malarkey DE,States JC,Cave MC

    更新日期:2014-09-15 00:00:00

  • 2,2,4-Trimethylpentane-induced nephrotoxicity. I. Metabolic disposition of TMP in male and female Fischer 344 rats.

    abstract::2,2,4-Trimethylpentane (TMP), a component of unleaded gasoline, causes nephrotoxicity in male, but not in female, rats. In the present study, male and female Fischer 344 rats were treated with a single oral dose of [14C]TMP (4.4 mmol/kg; 2 microCi/mmol). Radiolabeled material in kidney, liver, and plasma was determine...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Charbonneau M,Lock EA,Strasser J,Cox MG,Turner MJ,Bus JS

    更新日期:1987-11-01 00:00:00

  • Physiologically based kinetic modeling of bioactivation and detoxification of the alkenylbenzene methyleugenol in human as compared with rat.

    abstract::This study defines a physiologically based kinetic (PBK) model for methyleugenol (ME) in human based on in vitro and in silico derived parameters. With the model obtained, bioactivation and detoxification of methyleugenol (ME) at different doses levels could be investigated. The outcomes of the current model were comp...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Al-Subeihi AA,Spenkelink B,Punt A,Boersma MG,van Bladeren PJ,Rietjens IM

    更新日期:2012-05-01 00:00:00

  • Inactivation of the glutamine/amino acid transporter ASCT2 by 1,2,3-dithiazoles: proteoliposomes as a tool to gain insights in the molecular mechanism of action and of antitumor activity.

    abstract::The ASCT2 transport system catalyses a sodium-dependent antiport of glutamine and other neutral amino acids which is involved in amino acid metabolism. A library of 1,2,3-dithiazoles was designed, synthesized and evaluated as inhibitors of the glutamine/amino acid ASCT2 transporter in the model system of proteoliposom...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Oppedisano F,Catto M,Koutentis PA,Nicolotti O,Pochini L,Koyioni M,Introcaso A,Michaelidou SS,Carotti A,Indiveri C

    更新日期:2012-11-15 00:00:00

  • Evaluation of the pulmonary effects of wood smoke in guinea pigs by repeated CO2 challenges.

    abstract::Male, English smooth haired guinea pigs were exposed to thermal decomposition products, i.e., smoke, generated by heating Douglas fir in an open system. Various amounts of Douglas fir were placed in a furnace, at room temperature, and heated at a rate of 11 degrees C/min until completely decomposed. Major decompositio...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Wong KL,Stock MF,Malek DE,Alarie Y

    更新日期:1984-08-01 00:00:00

  • Opposing roles for caspase and calpain death proteases in L-glutamate-induced oxidative neurotoxicity.

    abstract::Oxidative glutamate toxicity in HT22 murine hippocampal cells is a model for neuronal death by oxidative stress. We have investigated the role of proteases in HT22 cell oxidative glutamate toxicity. L-glutamate-induced toxicity was characterized by cell and nuclear shrinkage and chromatin condensation, yet occurred in...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Elphick LM,Hawat M,Toms NJ,Meinander A,Mikhailov A,Eriksson JE,Kass GE

    更新日期:2008-10-15 00:00:00

  • Neocarzinostatin-induced Rad51 nuclear focus formation is cell cycle regulated and aberrant in AT cells.

    abstract::DNA double-stranded breaks are the most detrimental form of DNA damage and, if not repaired properly, may lead to an accumulation of chromosomal aberrations and eventually tumorigenesis. Proteins of the Rad51/Rad52 epitasis group are crucial for the recombinational repair of DNA double-stranded breaks, whereas the Rad...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Yuan SS,Yang YK,Chen HW,Chung YF,Chang HL,Su JH

    更新日期:2003-11-01 00:00:00

  • NURA: A curated dataset of nuclear receptor modulators.

    abstract::Nuclear receptors (NRs) are key regulators of human health and constitute a relevant target for medicinal chemistry applications as well as for toxicological risk assessment. Several open databases dedicated to small molecules that modulate NRs exist; however, depending on their final aim (i.e., adverse effect assessm...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Valsecchi C,Grisoni F,Motta S,Bonati L,Ballabio D

    更新日期:2020-11-15 00:00:00

  • AOP-DB: A database resource for the exploration of Adverse Outcome Pathways through integrated association networks.

    abstract::The Adverse Outcome Pathway (AOP) framework describes the progression of a toxicity pathway from molecular perturbation to population-level outcome in a series of measurable, mechanistic responses. The controlled, computer-readable vocabulary that defines an AOP has the ability to, automatically and on a large scale, ...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Pittman ME,Edwards SW,Ives C,Mortensen HM

    更新日期:2018-03-15 00:00:00

  • Protective role of dietary butylated hydroxyanisole against chemical-induced acute liver damage in mice.

    abstract::Prior consumption of a diet containing the food antioxidant, butylated hydroxyanisole (BHA), by female mice prevented the development of or minimized the acute liver damage caused by monocrotaline, acetaminophen, or bromobenzene. In contrast, neither the incidence nor the severity of carbon tetrachloride-induced hepat...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Miranda CL,Henderson MC,Schmitz JA,Buhler DR

    更新日期:1983-06-15 00:00:00

  • Effect of dietary acid or aluminum on growth and growth-related hormones in young chickens.

    abstract::The effect of two concentrations of dietary acid (sulfuric acid) or aluminum (aluminum sulfate) on growth and growth-related hormones was examined in a heavy (broiler) strain of chicken between 4 and 18 days old. Growth (body weight, average daily gain, and tibial length) in chicks receiving either dietary acid or alu...

    journal_title:Toxicology and applied pharmacology

    pub_type: 杂志文章


    authors: Capdevielle MC,Scanes CG

    更新日期:1995-07-01 00:00:00