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The effect of competitive and non‐linear plasma protein binding on the stereoselective disposition and metabolic inversion of ibuprofen in healthy subjects
Author(s) -
Smith David E.,
Paliwal Jyoti K.,
Cox Steven R.,
Berardi Rosemary R.,
DunnKucharski Valerie A.,
Elta Grace H.
Publication year - 1994
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510150703
Subject(s) - ibuprofen , stereoselectivity , chemistry , enantiomer , pharmacokinetics , pharmacology , plasma concentration , stereochemistry , chromatography , biochemistry , medicine , catalysis
The stereoselective disposition and metabolic inversion of ibuprofen were 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(−)‐ibuprofen, 300 mg S(+)‐ibuprofen, 300 mg R(−)‐ + 300mg 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 for all stereoisomeric drug species. Likewise, the unbound partial clearances of S(+)‐ibuprofen were greater for most stereoisomeric drug species. There was also less difference among treatment groups when partial clearances were referenced to unbound as opposed to total plasma concentrations of enantiomer. The unbound intrinsic clearance and fractional inversion of R(−)‐ibuprofen were unchanged across the four treatments, and chiral inversion was systemic, averaging 69%. In conclusion, stereoselective differences exist for the partial and composite clearances 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 non‐linear binding.