Ibuprofen Enantiomers Research Articles

Pharmacokinetic analysis of the enantiomeric inversion of chiral nonsteroidal antiinflammatory drugs.

Equations describing plasma concentration-time courses of the individual enantiomers of chiral 2-arylpropionic acid nonsteroidal antiinflammatory drugs were derived from a general model. The model assumes first-order absorption and elimination of the enantiomers with presystemic and/or systemic R-to-S enantiomeric inversion. Utilizing reported pharmacokinetic parameters, plasma concentrations of the enantiomers of ibuprofen (IB) were simulated. In the case of presystemic inversion, S:R plasma concentration ratios remained constant after an initial rise; the ratio progressively increased with time, however, when systemic inversion was assumed. Under the assumption of simultaneous systemic and presystemic inversion, the increase in the ratio in the postabsorptive phase was preceded by a steeper increase during absorption. Furthermore, it was shown that perturbation of IB absorption from the gastrointestinal tract may serve as an important discriminative measure for identification of the inversion site. For systemic and presystemic inversions, negative and positive sigmoidal relationships, respectively, were observed between the S:R concentration ratio 5 hr after drug administration and the time to reach the maximum plasma concentration. The applicability of the model to previously reported IB data is discussed.

Determination of the enantiomeric composition of ibuprofen in human plasma by high-performance liquid chromatography

A normal-phase high-performance liquid chromatographic method, using a hexane-ethyl acetate solvent system, for the determination of the enantiomeric composition of ibuprofen in human plasma is described. The method is based on the resolution of the diastereoisomeric amides formed on reaction of the ibuprofen enantiomers with S-1-(naphthen-1-yl) ethylamine using p-chlorophenoxy-acetic acid as internal standard. The application of the method for the determination of the enantiomeric composition of ibuprofen in human plasma following the repeated oral administration of the drug to two volunteers is reported. The plasma concentrations of the S-(+) enantiomer were always greater than that of the R-(—), the ratio of the areas under the enantiomer plasma concentration-time curves ( S/R) being 1.8 and 1.6.

The stereoselective uptake of ibuprofen enantiomers into adipose tissue

The stereoselective uptake of ibuprofen enantiomers into adipose tissue

Stereoselective disposition of ibuprofen enantiomers in man.

This study has examined the stereoselective disposition of the enantiomers of ibuprofen in four healthy male subjects following separate administration of racemic ibuprofen (800 mg) and of each enantiomer (400 mg). A mean of 63 +/- 6% of an administered dose of R(-) ibuprofen was stereospecifically inverted to the S(+) enantiomer. There were no measurable inversion of the S(+) to R(-) ibuprofen. The kinetics of the individual enantiomers were altered by concurrent administration of the respective optical antipode. It is likely that this change reflects an interaction between the enantiomers at plasma protein binding sites. It was found that formation of ester glucuronide conjugates stereoselectively favoured the S(+) enantiomer. The data have demonstrated that the pharmacokinetics of ibuprofen and other alpha-methylarylacetic acids cannot be interpreted adequately without studying the pharmacokinetics of the individual enantiomers.

Application of high-performance liquid chromatographic chiral stationary phases to pharmaceutical analysis structural and conformational effects in the direct enantiomeric resolution of α-methylarylacetic acid antiinflammatory agents

A series of four α-methylarylacetic acids of pharmaceutical interest were directly resolved as enantiomeric amide derivatives on a high-performance liquid chromatographic chiral stationary phase consisting of covalently bound ( R)-N-(3,5-dinitrobenzoyl)phenylglycine. Enantiomers of ibuprofen, naproxen fenoprofen and benoxaprofen all exhibited optimum separation (α = 1.12, 1.23, 1.12 and 1.10, respectively) as 1-naphthalenemethylamides. Derivatives of ibuprofen were studied in detail; measurable separations were observed for secondary and tertiary amides of diverse structural types, but not for the primary amide or for ester derivatives. The results, which are consistent with an interaction model involving stacking of amide dipoles, with or without supplementary π—π and hydrogen-bonding effects, appear to be strongly dependent on conformational requirements of both the solute and the chiral stationary phase.