Efficient Performance of Chiral Boron Nitride Nanotubes as Suitable Selector for Separation of Ibuprofen Enantiomers Using DFT-D3 Calculations and Molecular Dynamics Simulation

The separation of ibuprofen enantiomers and the interaction between right-handed (R) and left-handed (S) isomers of ibuprofen with the outer surface as well as internal sidewall of a chiral boron nitride nanotube (BNNT(10, 5)) was evaluated. The geometry optimizations and total energy calculations were performed with DFT-D3/revPBE-GGA method for various adsorption configurations. Our first-principles findings showed that interaction strength of the incorporated enantiomers into the BNNTs was higher than ones adsorbed onto the outer surface of nanotube. Also, the interaction energy difference between two enantiomers interacting with inside and outside of the BNNT was about 0.63 and 1.25 kcal/mol, respectively. This finding indicated the more ability of outer surface of BNNT in efficient enantioseparation of Ibuprofen isomers rather than inner site. Furthermore, in order to model a realistic system, molecular dynamics (MD) simulation was performed at room temperature, and the results were consisted with the DFT-D3 findings. The nudged elastic band (NEB) method was also used to evaluate the activation energy barrier for incorporation of ibuprofen into the BNNT cavity. Our molecular simulation findings are reliable to offer beneficial information about the potential application of chiral BNNTs in enantiomer molecules adsorption and separation.

Enantioselective Determination Of S- And R-Isomers Of Ibuprofen In Plasma By Ultra-Performance Liquid Chromatography – Tandem Mass Spectrometry

A new method of enantioselective determination of S- and R-isomers of ibuprofen in human plasma by ultraperformance liquid chromatography with tandem mass spectrometric detection using solid-phase extraction was developed. For enantioselective separation of ibuprofen isomers, a LUX Cellulose-3 chiral chromatographic column was used. Complete separation of the enathiomer peaks is achieved in the isocratic elution conditions with a mobile phase ratio of 0.05 % formic acid solution (%): methanol (%) = 30 : 70 (v/v) and a flow rate of 0.2 mL/min. The mass spectrometric detection was performed at negative ionization mode with multiple reaction monitoring, using the transitions at 205.13 > 161.14 Da and 208.09 > 164.03 Da for ibuprofen enantiomers and deuterated ibuprofen (internal standard), respectively. The method validation included the evaluation of the selectivity, linearity, lower limit of quantification (LLOQ), within-run and between-run precision and accuracy. The LLOQ for the two enantiomers was 100 ng/mL in plasma. The calibration curves showed good linearity of each enantiomers in the ranges from 100 to 60000 ng/mL. The method was successfully applied to a pharmacokinetic study of ibuprofen enantiomers in human plasma.

AKR1D1*36 C>T (rs1872930) allelic variant is associated with variability of the CYP2C9 genotype predicted pharmacokinetics of ibuprofen enantiomers – a pilot study in healthy volunteers

The relative contribution of CYP2C9 allelic variants to the pharmacokinetics (PK) of ibuprofen (IBP) enantiomers has been studied extensively, but the potential clinical benefit of pharmacogenetically guided IBP treatment is not evident yet. The role of AKR1D1*36C>T (rs 1872930) allelic variant in interindividual variability of CYP450 mediated drug metabolism was recently elucidated. A total of 27 healthy male subjects, volunteers in IBP single-dose two-way cross-over bioequivalence studies were genotyped for CYP2C9*2, CYP2C9*3 and AKR1D1*36 polymorphisms. The correlation between CYP2C9 and AKR1D1 genetic profile and the PK parameters for S-(+) and R-(−)-IBP was evaluated. Remarkable changes in the PK values pointing to reduced CYP2C9 enzyme activity were detected only in the CYP2C9*2 allelic variant carriers. Statistically significant association between the AKR1D1*36 allele and the increased IBP metabolism (low AUC0-t and 0–∞, high Cltot and short tmax values for both enantiomers) was observed in subjects carrying the CYP2C9 *1/*3 or CYP2C9*1/*1 genotype. The clinical value of concomitant CYP2C9 and AKR1D1 genotyping has to be further verified.