Exploring potential energy surfaces to reach saddle points above convex regions.

Saddle points on high-dimensional potential energy surfaces (PES) play a determining role in the activated dynamics of molecules and materials. Building on approaches dating back more than 50 years, many open-ended transition-state search methods have been developed to follow the direction of negative curvature from a local minimum to an adjacent first-order saddle point. Despite the mathematical justification, these methods can display a high failure rate: using small deformation steps, up to 80% of the explorations can end up in a convex region of the PES, where all directions of negative curvature vanish, while if the deformation is aggressive, a similar fraction of attempts lead to saddle points that are not directly connected to the initial minimum. In high-dimension PES, these reproducible failures were thought to only increase the overall computational cost, without having any effect on the methods' capacity to find all saddle points surrounding a minimum. Using activation-relaxation technique nouveau (ARTn), we characterize the nature of the PES around minima, considerably expanding on previous knowledge. We show that convex regions can lie on activation pathways and that not exploring beyond them can introduce significant bias in the saddle-point search. We introduce an efficient approach for traversing the convex regions, almost eliminating exploration failures, while multiplying by almost 10 the number of identified unique and connected saddle points as compared to the standard ARTn, thus underlining the importance of correctly handling convex regions for completeness of saddle point explorations.

Collective dipole effects in ionic transport under electric fields.

In the context of ionic transport in solids, the variation of a migration barrier height under electric fields is traditionally assumed to be equal to the classical electric work of a point charge that carries the transport charge. However, how reliable is this phenomenological model and how does it fare with respect to Modern Theory of Polarization? In this work, we show that such a classical picture does not hold in general as collective dipole effects may be critical. Such effects are unraveled by an appropriate polarization decomposition and by an expression that we derive, which defines the equivalent polarization-work charge. The equivalent polarization-work charge is not equal neither to the transported charge, nor to the Born effective charge of the migrating atom alone, but it is defined by the total polarization change at the transition state. Our findings are illustrated by oxygen charged defects in MgO and in SiO2.

Strain-driven diffusion process during silicon oxidation investigated by coupling density functional theory and activation relaxation technique.

The reaction of oxygen molecules on an oxidized silicon model-substrate is investigated using an efficient potential energy hypersurface exploration that provides a rich picture of the associated energy landscape, energy barriers, and insertion mechanisms. Oxygen molecules are brought in, one by one, onto an oxidized silicon substrate, and accurate pathways for sublayer oxidation are identified through the coupling of density functional theory to the activation relaxation technique nouveau, an open-ended unbiased reaction pathway searching method, allowing full exploration of potential energy surface. We show that strain energy increases with O coverage, driving the kinetics of diffusion at the Si/SiO2 interface in the interfacial layer and deeper into the bulk: at low coverage, interface reconstruction dominates while at high coverage, oxygen diffusion at the interface or even deeper into the bottom layers is favored. A changing trend in energetics is observed that favors atomic diffusions to occur at high coverage while they appear to be unlikely at low coverage. Upon increasing coverage, strain is accumulated at the interface, allowing the oxygen atom to diffuse as the strain becomes large enough. The observed atomic diffusion at the interface releases the accumulated strain, which is consistent with a layer-by-layer oxidation growth.

On the early stage of aluminum oxidation: an extraction mechanism via oxygen cooperation.

We propose a barrierless mechanism for describing the oxidation of Al(111) in which oxygen atoms located on the outer surface extract aluminum atoms of the surface layers through local cooperation of other pre-adsorbed oxygen atoms. We show the details of this complex chemical process that kinetically competes with the non-destructive formation of an oxygen monolayer onto the Al surface, thus elucidating the initial aluminum oxidation regime. We demonstrate that further stripping of the complete surface Al layer is consistent with both (i) the formation of a defective alumina structure and (ii) an oxide capping layer preventing further oxidation at low temperature.

Difficulty for oxygen to incorporate into the silicon network during initial O2 oxidation of Si(100)-(2x1).

First principles calculations and scanning tunneling microscopy studies of the oxidation of Si(100)-(2x1) surfaces by molecular oxygen reveal that the surface silanone (O)(Si=O) species is remarkably stable, constituting the key intermediate for initial oxidation. The propensity for oxygen to remain within the top surface layer as opposed to incorporating within Si-Si backbonds is surprisingly high. This resistance to incorporation into a cubic lattice even at higher coverages could be a factor to facilitate surface amorphization in subsequent steps.

Pharmacokinetics, metabolism, excretion and plasma protein binding of 14C-levofloxacin after a single oral administration in the Rhesus monkey.

Levofloxacin's metabolism, excretion, and in vitro plasma protein binding, together with its pharmacokinetics, were studied in the Rhesus monkey in support of an anthrax efficacy study in this species. Three males and three female Rhesus monkeys were dosed with a single oral dose of 14C-levofloxacin at 15 mg kg-1 (2 MBq kg-1). Following dose administration, blood samples were collected up to 48 h post-dose, and urine and faeces were quantitatively collected up to 168 h post-dose. Blood, plasma, urine, and faeces were analysed for total radioactivity. Metabolite profiling and identification was performed using radio-high-performance liquid chromatography (HPLC) and liquid chromatography coupled with tandem mass spectrometry detection (LC-MS/MS). Additionally, the plasma protein binding of levofloxacin was determined in vitro by means of equilibrium dialysis. Peak plasma levels of total radioactivity and levofloxacin were rapidly reached after oral administration with a total radioactivity blood: plasma ratio close to unity. The elimination half-life of levofloxacin was estimated at about 2 h. Total radioactivity was mainly excreted in urine (about 57-86% of the dose) with faecal excretion accounting for only a minor fraction of the total amount of excreted radioactivity (about 7.4-14.7%). In the plasma, the majority of total radioactivity was accounted for by levofloxacin. In addition, two minor metabolites, i.e. levofloxacin n-oxide and presumably a glucuronide conjugate of levofloxacin, were detected. In the urine, five components were found, with levofloxacin being the major component. Minor metabolites included desmethyl levofloxacin, levofloxacin n-oxide, and a glucuronide conjugate of levofloxacin. In the faeces, the major analyte was a polar metabolite, tentatively identified as a levofloxacin glucuronide. The in vitro plasma protein binding was low (on average 11.2%) and independent of concentration (1.0-10.0 microg ml-1). No sex differences were noted in any of the investigations. The present data indicated that the metabolism and excretion pattern, and also the in vitro plasma protein binding of levofloxacin in the Rhesus monkey, were comparable with those previously reported in man, hereby supporting the use of this animal species in the efficacy evaluation of levofloxacin against inhalation anthrax. The shorter half-life of levofloxacin in the Rhesus monkey relative to man (2 versus 7 h) prompted the development of an alternative dosing strategy for use in the efficacy study.

Metoprolol-paroxetine interaction in human liver microsomes: stereoselective aspects and prediction of the in vivo interaction.

This study in human liver microsomes was undertaken to establish whether paroxetine stereoselectively inhibits the oxidative metabolism of metoprolol in vitro, and whether the in vivo observed magnitude of the paroxetine-metoprolol interaction was predictable from these in vitro data. Two distinct approaches were used: inhibitory effect of paroxetine on 1) the formation of alpha-hydroxymetoprolol and O-desmethylmetoprolol from the individual metoprolol enantiomers and 2) on the depletion of the enantiomers from the incubation mixture. Nonspecific binding of both metoprolol and paroxetine to human liver microsomes was also investigated. Whereas metoprolol displayed negligible binding, paroxetine was extensively bound to microsomal proteins. This was taken into account in order to obtain unbiased K(i) values and unbound concentrations of paroxetine. In the substrate depletion experiments, the intrinsic clearance (CL(int)) of (R)-metoprolol was larger than that of (S)-metoprolol. Paroxetine caused a concentration-dependent decrease in CL(int) of both enantiomers and abolished the stereoselectivity. In the metabolite formation experiments paroxetine did not stereoselectively affect alpha-hydroxylation, but preferentially inhibited the O-demethylation of the (R)-enantiomer versus the (S)-enantiomer. The use of unbound paroxetine concentrations in the two in vitro methods yielded comparable predicted increases in area under the curve (1.7-1.9 and 2.2-2.5 for (S)- and (R)-metoprolol, respectively) but underestimated the in vivo observed changes of about 7- and 10-fold, respectively. In conclusion, this study showed that paroxetine abolishes the stereoselective metabolism of metoprolol due to a stereoselective inhibition of the O-demethylation toward (R)-metoprolol. Furthermore, the extent of the in vivo metoprolol-paroxetine interaction was substantially underestimated by either one of the two in vitro approaches used when a competitive mechanism was assumed.

Effect of selective serotonin reuptake inhibitors on the oxidative metabolism of propafenone: in vitro studies using human liver microsomes.

Propafenone is mainly metabolized by CYP2D6 to form 5-hydroxypropafenone (5-OHP) and to a minor extent by CYP1A2 and CYP3A4 to form N-depropylpropafenone (N-DPP). The in vitro inhibitory effect of selective serotonin reuptake inhibitors (SSRIs) on the formation of both metabolites was studied, using human liver microsomes. The 5-OHP formation from racemic propafenone and from its individual enantiomers followed one-enzyme Michaelis-Menten kinetics. Incubation with the racemate yielded a mean Vmax of 64 pmol x min(-1) x mg(-1) and a mean Km of 0.12 microM (N = 3). Stereoselectivity in Vmax and Km values was observed, with (S)-propafenone displaying higher Km and Vmax values. N-DPP formation from racemic propafenone followed one-enzyme Michaelis-Menten kinetics and yielded a mean Vmax of 403 pmol x min(-1) x mg(-1) and a mean Km of 116 microM (N = 3). No stereoselectivity in propafenone N-dealkylation was observed. The influence of SSRIs and quinidine, a prototypical CYP2D6 inhbitor, on propafenone 5-hydroxylation was investigated. Quinidine was the most potent inhibitor, followed by fluoxetine, norfluoxetine, and paroxetine. Sertraline, desmethylsertraline, and fluvoxamine had only a moderate inhibitory effect, whereas citalopram displayed slight or no inhibition when racemic propafenone was used as substrate. Mean Ki values of quinidine, fluoxetine, norfluoxetine, and paroxetine were 0.13, 0.33, 0.55, and 0.54 microM, respectively (N = 3). Quinidine and paroxetine were also tested as inhibitors using the individual enantiomers, but no stereoselectivity was observed. Among the SSRIs tested, only fluvoxamine substantially inhbited propafenone N-dealkylation with a mean IC50 of 7.0 microM (N = 3). There was a more pronounced inhibitory effect of fluvoxamine on (R)-propafenone than on (S)-propafenone N-dealkylation. In conclusion, these in vitro data suggest that an in vivo interaction between propafenone and the SSRIs, fluoxetine and paroxetine, can be expected, which can lead to clinically relevant beta-blockade and an increased risk of side effects in the central nervous system. An interaction with fluvoxamine may be of importance in poor metabolizers for CYP2D6.

Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers.

OBJECTIVE: To investigate the effect of multiple-dose paroxetine intake on the stereoselective pharmacokinetics and the pharmacodynamics of metoprolol. METHODS: We conducted an open trial with two sessions in eight healthy male volunteers. Racemic metoprolol (100 mg single oral dose) was administered before and after paroxetine treatment (20 mg/day for 6 days). The (R)- and (S)-metoprolol pharmacokinetics, metoprolol metabolic ratio (MR), exercise heart rate and blood pressure were assessed for 12 (pharmacodynamic data) to 24 (pharmacokinetic data) hours after each metoprolol intake. RESULTS: Paroxetine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC) of (R)- and (S)-metoprolol significantly (169 to 1,340 ng x h/mL [P < .001] and 279 to 1,418 ng x h/mL [P < .001], respectively), with an approximately twofold increase in both maximum plasma concentration and terminal elimination half-life. Furthermore, the (S)/(R) AUC ratio was significantly decreased, from 1.72 to 1.07 (P < .001). The mean metoprolol MR was significantly increased, from 0.17 to 5.69 (P < .05). The AUC of the metoprolol-induced decrease in exercise heart rate versus time curve was increased, with 46% (P < .01) after multiple-dose paroxetine intake, reaching significance from 6 hours after metoprolol intake, illustrating a more sustained beta-blockade. Similar results were obtained for the effect on exercise systolic blood pressure. Multiple-dose metoprolol administration combined with paroxetine can lead to an accumulation of the beta-blocking (S)-enantiomer of metoprolol, possibly resulting in unacceptable bradycardia, loss of cardioselectivity, or both. CONCLUSION: Multiple-dose paroxetine intake affects both metoprolol pharmacokinetics and pharmacodynamics and suggests that when paroxetine is added to an ongoing metoprolol therapy, caution is warranted and a reduction of the metoprolol dose may be required to prevent undesired adverse effects.

Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes.

OBJECTIVE: To investigate the in vitro potential of selective serotonin reuptake inhibitors (SSRIs) to inhibit two CYP2C9-catalysed reactions, tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. METHODS: The formation of 4-hydroxytolbutamide from tolbutamide and that of 7-hydroxywarfarin from (S)-warfarin as a function of different concentrations of SSRIs and some of their metabolites was studied in microsomes from three human livers. RESULTS: Both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation followed one enzyme Michaelis-Menten kinetics. Kinetic analysis of 4-hydroxytolbutamide formation yielded a mean apparent Michaelis-Menten constant (Km) of 133 microM and a mean apparent maximal velocity (Vmax) of 248 pmol x min(-1) x mg(-1); formation of 7-hydroxywarfarin yielded a mean Km of 3.7 microM and a mean Vmax of 10.5 pmol x min(-1) x mg(-1). Amongst the SSRIs and some of their metabolites tested, only fluvoxamine markedly inhibited both reactions. The average computed inhibition constant (Ki) values and ranges of fluvoxamine when tolbutamide and (S)-warfarin were used as substrate, were 13.3 (6.4-17.3) microM and 13.0 (8.4-18.7) microM, respectively. The average Ki value of fluoxetine for (S)-warfarin 7-hydroxylation was 87.0 (57.0-125) microM. CONCLUSION: Amongst the SSRIs tested, fluvoxamine was shown to be the most potent inhibitor of both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. Fluoxetine, norfluoxetine, paroxetine, sertraline, desmethylsertraline, citalopram, desmethylcitalopram had little or no effect on CYP2C9 activity in vitro. This is consistent with in vivo data indicating that amongst the SSRIs, fluvoxamine has the greatest potential for inhibiting CYP2C9-mediated drug metabolism.

ECG changes and plasma concentrations of propafenone and its metabolites in a case of severe poisoning.

CASE REPORT: Propafenone is a class IC antiarrhythmic agent metabolized into two major metabolites, 5-hydroxypropafenone and N-depropylpropafenone. The potency of 5-hydroxypropafenone to block fast sodium channels is comparable to that of its parent. We report the positive correlation between plasma concentrations and electrocardiographic changes in a patient with severe oral self-poisoning. Serial ECG changes were measured and plasma concentrations were determined by high-performance liquid chromatography. The initial plasma concentrations of propafenone were in the toxic range and correlated with the widening of the QRS-complex. The slow decline in concentration during this first phase might relate to saturation of the isoenzyme CYP2D6. The half-life of propafenone, calculated from the second phase, was approximately 3 hours, defining the patient as a fast metabolizer. The initial concentrations of the metabolite N-depropylpropafenone were surprisingly higher than those of 5-hydroxypropafenone which may also be due to saturation of CYP2D6.