Comparative pharmacology of s(+)-ibuprofen and (RS)-ibuprofen
Comparative pharmacology of s(+)-ibuprofen and (RS)-ibuprofen
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DOI：
10.1007/bf03342662
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发表时间：
2001-11-01
影响因子：
3.4
通讯作者：
Evans, AM
中科院分区：
文献类型：
--
作者：
Evans, AM
外消旋布洛芬含有等量的R（-）-布洛芬和S（+）-布洛芬，已被用作抗炎和镇痛剂超过30年。尽管S（+）-对映体能够在临床相关浓度下抑制环氧合酶（考克斯），但R（-）-布洛芬不是考克斯抑制剂。因此，布洛芬的两种对映体在药理学性质方面不同，可以被视为两种不同的“药物”。它们的代谢特征也不同。例如，R（-）-布洛芬参与脂质代谢途径，并与内源性脂肪酸一起沿着掺入甘油三酯中，S（+）-布洛芬似乎不参与这些不寻常的代谢反应，这就是为什么S（+）-布洛芬被认为比外消旋布洛芬代谢“更清洁”的原因。当将外消旋布洛芬给予人类时，R（-）-布洛芬剂量的大部分（50%-60%）经历“代谢转化”以产生S（+）-布洛芬。在此基础上，有人认为，为了获得与给定剂量的外消旋布洛芬相当的临床效果，S（+）布洛芬的剂量需要约为外消旋布洛芬剂量的75%。然而，这种“药代动力学”原理没有考虑到转化不是瞬时的，个体间转化程度存在差异，以及转化动力学可能因给药情况而异。例如，当给经历急性疼痛的患者服用RACTIVE时，倒置的程度似乎会减少。最近的研究表明，外消旋布洛芬的临床益处可以来自于以外消旋布洛芬的一半剂量施用单一S（+）-对映体。例如，已发现200 mg S（+）-布洛芬在缓解牙痛方面上级或至少相当于400 mg雷帕霉素。考虑了S（+）-布洛芬高于预期疗效的可能解释。
Racemic ibuprofen, which contains equal quantities of R(-)-ibuprofen and S(+)-ibuprofen, has been used as an anti-inflammatory and analgesic agent for over 30 years. Although the S(+)-enantiomer is capable of inhibiting cyclooxygenase (COX) at clinically relevant concentrations, R(-)-ibuprofen is not a COX inhibitor. The two enantiomers of ibuprofen are therefore different in terms of their pharmacological properties and may be regarded as two different 'drugs'. They also differ in terms of their metabolic profiles. For example, R(-)-ibuprofen becomes involved in pathways of lipid metabolism and is incorporated into triglycerides along with endogenous fatty acids S(+)-Ibuprofen does not appear to become involved in these unusual metabolic reactions, which is why S(+)-ibuprofen is regarded as being metabolically 'cleaner' than racemic ibuprofen. When racemic ibuprofen is given to humans, a substantial fraction of the dose of R(-)-ibuprofen (50%-60%) undergoes 'metabolic inversion' to yield S(+)-ibuprofen. On this basis, it has been argued that to obtain clinical effects that are comparable to those of a given dose of racemic ibuprofen, the dose of S(+)ibuprofen would need to be about 75% of the dose of the racemate. However, this 'pharmacokinetic' rationale does not take into account the fact that inversion is not instantaneous, that there is variability in the extent of inversion between individuals, and that the kinetics of inversion may differ depending on the dosing situations. For example, the extent of inversion appears to be reduced when the racemate is given to patients experiencing acute pain. Recent studies have demonstrated that the clinical benefits of racemic ibuprofen can be derived from the administration of the single S(+)-enantiomer at a dose that is half that of the racemate. For example, 200 mg of S(+)-ibuprofen has been found to be superior or at least equivalent to 400 mg of the racemate in the relief of dental pain. Possible explanations for this higher than expected efficacy of S(+)-ibuprofen are considered.