Plasma protein binding (PPB) is an important parameter for a drug's efficacy and safety that needs to be investigated during each drug-development program. Even though regulatory guidance exists to study the extent of PPB before initiating clinical studies, there are no detailed instructions on how to perform and validate such studies. To explore how PPB studies involving bioanalysis are currently executed in the industry, the European Bioanalysis Forum (EBF) has conducted three surveys among their member companies: PPB studies in drug discovery (Part I); in vitro PPB studies in drug development (Part II); and in vivo PPB studies in drug development. This paper reflects the outcome of the three surveys, which, together with the team discussions, formed the basis of the EBF recommendation. The EBF recommends a tiered approach to the design of PPB studies and the bioanalysis of PPB samples: 'PPB screening' experiments in (early) drug discovery versus qualified/validated procedures in drug development.

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CHO+ ions are made by electron impact on CD3OH in the source (ICR1) of a tandem ion cyclotron resonance spectrometer. These ions are injected into a differentially pumped analysis cell (ICR2) where they are reacted with a number of small molecules. The internal energy distribution in the CHO+ ions is obtained using total reactivity studies with neutral molecules of varying proton affinities. About 40% of the CHO+ ions react with D2 either by proton transfer to form D2H+ or isotopic exchange to form CDO+ ions. A series of experiments are performed that conclusively show these ions are the HOC+ isomer and the exchange is due to the catalytic isomerization reaction HOC++D2→DCO++HD which is approximately 37 kcal/mol exothermic. The product DCO+ ions are vibrationally cool indicating the reaction releases most of its energy as kinetic energy. Absolute rate constants for reactions of CHO+ ions with the neutrals 13CO, 15N2, CO2, O2, D2, and Ar are reported. HOC+ reacts with D2 at about 30% of the collision rate. This rate decreases with increasing HOC+ kinetic energy in the range 0.025 to 0.44 eV. The two products of the reaction are D2H+/CO and DCO+/HD with DCO+/HD comprising ∼42% of the products for the HOC+ ions formed from CD3OH. Phase space theory calculations are performed to determine the barrier to catalytic isomerization. The data are best fit with a barrier between 0.0 and −0.05 eV relative to the HOC+/D2 asymptotic energy. A barrier of this magnitude yields reaction rate constants at interstellar temperatures of at least 10% of the collision rate constant (i.e., k>1×10−10 cm3/s), and could explain why so little HOC+ is observed in interstellar clouds.

The results of a study of the photodissociation of the carbon dioxide ion-molecule cluster, (C02)2+, from 458 to 650 nm are presented. The experiments were performed with a high-energy ion beam crossed with a laser beam. C02+ was the only product observed. Photodissociation kinetic energy release distributions and angular distributions were measured. The kinetic energy release distributions are bimodal indicating that C02+ is generated by two mechanisms. The product peak shapes were simulated by the measured product velocity distributions and two product angular distributions of the form 1 + ß 2(cos ) with ß = 1.0 for the high-energy component in the kinetic energy release distribution and ß = 0.25 for the low-energy component. The results suggest that the mechanisms leading to C02+ are rapid fragmentation on a repulsive surface on a time scale which is short compared to a rotational period and statistical vibrational predissociation (statistical unimolecular dissociation) of highly vibrationally excited ground electronic state (C02)2+ on a time scale which may be longer than a rotational period. Phase space calculations of the statistical vibrational predissociation component compare well with our results. The analysis suggests that 11% of the C02+ product is formed by statistical vibrational predissociation at 650 nm and 22% at 458 nm; the remainder is formed by direct dissociation from a repulsive surface. The average product relative kinetic energy increases with increasing photon energy and varies in a linear fashion with the available energy.