THE EFFECT OF COMPETITIVE AND NONLINEAR PLASMA-PROTEIN BINDING ON THESTEREOSELECTIVE DISPOSITION AND METABOLIC INVERSION OF IBUPROFEN IN HEALTHY-SUBJECTS

The stereoselective disposition and metabolic inversion of ibuprofen w ere studied in 12 healthy subjects under conditions of competitive and non-linear plasma protein binding. Each subject received each of four oral treatments according to a Latin-square design: 300 mg R(-)-ibupr ofen, 300 mg S(+)-ibuprofen, 300 mg R(-)- + 300 mg S(+)ibuprofen, and 300 mg R(-)-+600 mg S(+)-ibuprofen. For a given treatment, the partial clearance of S(+)-ibuprofen was greater than that of R(-)-ibuprofen f or all stereoisomeric drug species. Likewise, the unbound partial clea rances of S(+)-ibuprofen were greater for most stereoisomeric drug spe cies. There was also less difference among treatment groups when parti al clearances were referenced to unbound as opposed to total plasma co ncentrations of enantiomer. The unbound intrinsic clearance and fracti onal inversion of R(-)-ibuprofen were unchanged across the four treatm ents, and chiral inversion was systemic, averaging 69%. In conclusion, stereoselective differences exist for the partial and composite clear ances of R(-)- and S(+)-ibuprofen even when corrected for differences in plasma protein binding. However, differences among treatment groups for a particular elimination pathway are largely due to ibuprofen's n on-linear binding.