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ABSTRACT:The risk of idiosyncratic drug toxicity (IDT) is of great concern to the pharmaceutical industry. Current hypotheses based on retrospective studies suggest that the occurrence of IDT is related to covalent binding and daily dose. We determined the covalent binding of 42 radiolabeled drugs in three test systems (human liver microsomes and hepatocytes in vitro and rat liver in vivo) to assess the risk of IDT. On the basis of safety profiles given in official documentation, tested drugs were classified into the safety categories of safe, warning, black box warning, and withdrawn. The covalent binding in each of the three test systems did not distinguish the safety categories clearly. However, when the log-normalized covalent binding was plotted against the log-normalized daily dose, the distribution of the plot in the safety categories became clear. An ordinal logistic regression analysis indicated that both covalent binding and daily dose were significantly correlated with safety category and that covalent binding in hepatocytes was the best predictor among the three systems. When two separation lines were drawn on the correlation graph between covalent binding in human hepatocytes and daily dose by a regression analysis to create three zones, 30 of 37 tested drugs were located in zones corresponding to their respective classified safety categories. In conclusion, we established a zone classification system using covalent binding in human hepatocytes and daily dose for the risk assessment of IDTs.

Hepatotoxicity of diclofenac has been known in experimental animals and humans but its mechanism has not been fully understood. The present study examined the role of mitochondrial permeability transition (MPT) in the pathogenesis of diclofenac-induced hepatocyte injury by using isolated mitochondria and primary culture hepatocytes from rats. Incubation of energized mitochondria with succinate in the presence of Ca 2؉ and diclofenac resulted in mitochondrial swelling, leakage of accumulated Ca 2؉ , membrane depolarization, and oxidation of nicotinamide adenine dinucleotide phosphate and protein thiol. All of these phenomena were suppressed by coincubation of the mitochondria with cyclosporin A, a typical inhibitor of MPT, showing that diclofenac opened the MPT pore. It was also suggested that reactive oxygen species probably generated during mitochondrial respiration and/or voltage-dependent mechanism was involved in MPT, which are proposed as mecha D iclofenac is a nonsteroidal anti-inflammatory drug (NSAID) widely used clinically. Hepatotoxicity is one of the side effects associated with the drug. Various mechanisms for the diclofenac-induced liver injury were proposed, but have not been fully understood. The diclofenac liver toxicity in humans is idiosyncratic, 1 and immunologic and metabolic idiosyncrasies have been suggested. 2,3 Thus, metabolic activation of this drug has been a focus, 4-6 and several reactive metabolites were proposed as candidates to contribute to the toxicity in experimental animals and humans. [7][8][9][10] On the other hand, we currently obtained the following evidence that diclofenac rather than its metabolite was responsible for the toxicity. Diclofenac toxicity to rat hepatocytes was not prevented by inhibiting its oxidation of conjugative metabolism. 11 NSAIDs including diclofenac that have a common chemical structure have hepatocyte toxicity, and these toxic NSAIDs depleted cellular adenosine triphosphate (ATP) before the enzyme leakage. 11 The toxic NSAIDs have been shown to be uncouplers of mitochondrial oxidative phosphorylation, which results in impairment of ATP synthesis. 12 Furthermore, rescue of hepatocytes from depletion of ATP conferred protection against hepatocyte injury induced by diclofenac. 13 It was thus concluded that the uncoupling property of diclofenac plays a crucial role in its hepatotoxicity, whereas an additional and/or alternative step is necessary to explain the mechanism for clinically observed idiosyncratic liver injury.Mitochondrial permeability transition (MPT) is recently focused as a mechanism for drug-induced hepatocyte necrosis and apoptosis. [14][15][16] The MPT represents an abrupt increase in permeability of the mitochondrial inner membrane to allow solutes with a molecular weight less than 1,500. 17 The MPT is promoted by the accumulation of excessive Ca 2ϩ and stimulated by various compounds and conditions. It leads to dissipation of membrane potential (⌬⌿), uncoupling, loss of preaccumulated Ca 2ϩ , and expansion of the matrix volume. Uncou...

A candidate for a soft dipole resonance, a dipole oscillation mode between a core cluster and a neutron skin, was observed at Ex = 4+/-1 MeV and with a width of 4+/-1 MeV in 6He via the 6Li( 7Li, 7Be) reaction at an incident energy of 65A MeV and forward scattering angles including 0 degrees. Its cross section is deduced to be sigma(0 degrees ) = 0.9+/-0.2 mb/sr. This value is comparable to that of the giant dipole resonance simultaneously measured.

Spin-isospin excitations inBi have been investigated using the Pb( He, t) Bi reaction at and near 6 -0' at R( He)=450 MeV. The microscopic structure of the Gamow-Teller resonance (GTR), the isobaric analog state (IAS), and the spin-Hip dipole (AL = 1) resonance (SDR) in Bi has been studied by observing their direct proton decays to the low-lying neutron-hole states in Pb. Decay protons were measured at backward angles in coincidence with tritons detected at and near O'. The total branching ratio for proton decay from the GTR is determined to be only 4.9+1.370. The total branching ratio for proton decay from the SDR amounts to 14.1+4.2'FD. The deduced total widths as well as the total and partial proton escape widths of the GTR and IAS are found to be in reasonable agreement with recent theoretical estimates obtained in the framework of the continuum Tamm-Dancoff approximation.PACS number(s): 24.30. Cz, 25.55.Kr, 27.80.+w, 29.30.Aj

ABSTRACT:Bioactivation of a drug to a reactive metabolite and its covalent binding to cellular macromolecules is believed to be involved in clinical adverse events, including idiosyncratic drug toxicities (IDTs). For the interpretation of the covalent binding data in terms of risk assessment, the in vitro and in vivo covalent binding data of a variety of drugs associated with IDTs or not were determined. Most of the "problematic" drugs, including "withdrawn" and "warning" drugs, exhibit higher human liver microsome (HLM) in vitro covalent binding yields than the "safe" drugs. Although some of the problematic drugs that are known to undergo bioactivation other than cytochrome P450-mediated oxidation exhibited only trace levels of HLM covalent binding like safe drugs, a rat in vivo covalent binding study could assess the bioactivation of such drugs. Furthermore, the tissue distribution/retention of the drugs was also examined by rat autoradiography (ARG). The residual radioactivity in the liver observed at 72 or 168 h postdose was found to be well correlated with the rat in vivo covalent binding to liver proteins; thus, the in vivo covalent binding yields of the drugs could be extrapolated from the retention profiles observed by means of ARG. Long-term retention of radioactivity in the bone marrow was observed with some drugs associated with severe agranulocytosis, suggesting a spatial relationship between the toxicity profile and drug distribution/retention. Taken together, the covalent binding and tissue distribution/retention data of the various marketed drugs obtained in the present study should be quite informative for the interpretation of data in terms of risk assessment.

Differential cross sections for transitions of known weak strength were measured with the (3He, t) reaction at 420 MeV on targets of 12C, 13C, 18O, 26Mg, 58Ni, 60Ni, 90Zr, 118Sn, 120Sn, and 208Pb. Using these data, it is shown that the proportionalities between strengths and cross sections for this probe follow simple trends as a function of mass number. These trends can be used to confidently determine Gamow-Teller strength distributions in nuclei for which the proportionality cannot be calibrated via beta-decay strengths. Although theoretical calculations in the distorted-wave Born approximation overestimate the data, they allow one to understand the main experimental features and to predict deviations from the simple trends observed in some of the transitions.

Charge-exchange reactions are an important tool for determining weak-interaction rates. They provide stringent tests for nuclear structure models necessary for modeling astrophysical environments such as neutron stars and core-collapse supernovae. In anticipation of (t, 3 He) experiments at 115 MeV/nucleon on nuclei of relevance (A∼ 40 − 120) in the late evolution of stars, it is shown via a study of the 26 Mg(t, 3 He) reaction that this probe is an accurate tool for extracting Gamow-Teller transition strengths. To do so, the data are complemented by results from the 26 Mg( 3 He,t) reaction at 140 MeV/nucleon which allows for a comparison of T=2 analog states excited via the mirror reactions. Extracted Gamow-Teller strengths from 26 Mg(t, 3 He) and 26 Mg( 3 He,t) are compared with those from 26 Mg(d, 2 He) and 26 Mg(p,n) studies, respectively. A good correspondence is found, indicating probe-independence of the strength extraction. Furthermore, we test shell-model calculations using the new USD-05B interaction in the sd-model space and show that it reproduces the experimental Gamow-Teller strength distributions well. A second goal of this work is to improve the understanding of the (t, 3 He) and ( 3 He,t) reaction mechanisms at intermediate energies since detailed studies are scarce. The Distorted-Wave Born Approximation is employed, taking into account the composite structures of the 3 He and triton particles. The reaction model provides the means to explain systematic uncertainties at the 10-20% level in the extraction of Gamow-Teller strengths as being due to interference between Gamow-Teller ∆L = 0, ∆S = 1 and ∆L = 2, ∆S = 1 amplitudes that both contribute to transitions from 0 + to 1 + states.