Smith D E, Paliwal J K, Cox S R, Berardi R R, Dunn-Kucharski V A, Elta G H
College of Pharmacy, University of Michigan, Ann Arbor 48109.
Biopharm Drug Dispos. 1994 Oct;15(7):545-61. doi: 10.1002/bdd.2510150703.
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(-)(-)+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 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.
在竞争性和非线性血浆蛋白结合条件下，对12名健康受试者中布洛芬的立体选择性处置和代谢转化进行了研究。每位受试者按照拉丁方设计接受四种口服治疗中的每一种：300毫克R(-)-布洛芬、300毫克S(+)-布洛芬、300毫克R(-)(-)+300毫克S(+)-布洛芬以及300毫克R(-)(-)+600毫克S(+)-布洛芬。对于给定的治疗，所有立体异构药物种类的S(+)-布洛芬的部分清除率均高于R(-)-布洛芬。同样，大多数立体异构药物种类的S(+)-布洛芬的未结合部分清除率更高。当部分清除率以对映体的未结合而非总血浆浓度为参考时，各治疗组之间的差异也更小。在四种治疗中，R(-)-布洛芬的未结合内在清除率和分数转化不变，且手性转化是全身性的，平均为69%。总之，即使校正了血浆蛋白结合差异，R(-)-和S(+)-布洛芬的部分清除率和综合清除率仍存在立体选择性差异。然而，特定消除途径的各治疗组之间的差异很大程度上归因于布洛芬的非线性结合。
