Kirchheiner Julia, Meineke Ingolf, Freytag Georg, Meisel Christian, Roots Ivar, Brockmöller Jürgen
Institute of Clinical Pharmacology, Charité, Humboldt University, Berlin, Germany.
Clin Pharmacol Ther. 2002 Jul;72(1):62-75. doi: 10.1067/mcp.2002.125726.
According to in vitro data, the polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) may be the major S-ibuprofen hydroxylase. In humans, there are 2 variants of CYP2C9 with a high population frequency. We studied their impact on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2.
Kinetics of an oral dose of 600 mg racemic ibuprofen were studied in 21 healthy volunteers with all combinations of the CYP2C9 variants *2 (arginine144cysteine) and *3 (isoleucine359leucine). Blood concentrations of racemic ibuprofen and of S-(+)-ibuprofen and R-(-)-ibuprofen were measured by HPLC, and thromboxane B(2) and prostaglandin E(2) were measured with use of an enzyme immunoassay. Data were evaluated with a population pharmacokinetic model that integrated pharmacogenetic information.
The pharmacokinetics of racemic and of S-ibuprofen depended on the CYP2C9 isoleucine359leucine amino acid polymorphism: population mean S-ibuprofen clearances were 3.25 L/h (95% confidence interval [CI], 2.84 to 3.73), 2.38 L/h (95% CI, 2.09 to 2.73), and 1.52 L/h (95% CI, 1.33 to 1.74) in carriers of the CYP2C9 genotypes *1/*1, *1/*3, and *3/*3, respectively. The CYP2C9 variant *2 exhibited no significant effect. Ex vivo formation of thromboxane B(2), reflecting cyclooxygenase type 1 inhibition, depended significantly on the CYP2C9 polymorphism. The maximal inhibition of thromboxane B(2) formation and the area under the effect-time curve were larger in carriers of the slow CYP2C9 genotypes *1/*3, *2/*3, and *3/*3 than in *1/*1 carriers; the same trend was observed for prostaglandin E(2), reflecting cyclooxygenase type 2 inhibition.
The reduced S-ibuprofen total clearance accompanied by increased pharmacodynamic activity may have medical impact in patients receiving ibuprofen.
根据体外数据，多态性细胞色素P450酶2C9（CYP2C9）可能是主要的S-布洛芬羟化酶。在人类中，有2种CYP2C9变体，其在人群中的频率较高。我们研究了它们对布洛芬药代动力学以及对环氧化酶1和2抑制作用的影响。
在21名健康志愿者中，研究了口服600 mg消旋布洛芬的药代动力学，这些志愿者具有CYP2C9变体2（精氨酸144半胱氨酸）和3（异亮氨酸359亮氨酸）的所有组合。通过高效液相色谱法测定消旋布洛芬、S-(+)-布洛芬和R-(-)-布洛芬的血药浓度，并用酶免疫分析法测定血栓素B2和前列腺素E2。数据采用整合了药物遗传学信息的群体药代动力学模型进行评估。
消旋布洛芬和S-布洛芬的药代动力学取决于CYP2C9异亮氨酸359亮氨酸氨基酸多态性：CYP2C9基因型*1/*1、1/3和3/3携带者的群体平均S-布洛芬清除率分别为3.25 L/h（95%置信区间[CI]，2.84至3.73）、2.38 L/h（95%CI，2.09至2.73）和1.52 L/h（95%CI，1.33至1.74）。CYP2C9变体2未显示出显著影响。反映环氧化酶1抑制作用的血栓素B2的体外形成显著取决于CYP2C9多态性。CYP2C9慢代谢基因型我/*3、*2/3和3/3携带者的血栓素B2形成的最大抑制作用和效应-时间曲线下面积大于1/*1携带者；反映环氧化酶2抑制作用 的前列腺素E2也观察到相同趋势。
S-布洛芬总清除率降低并伴有药效学活性增加，这可能对接受布洛芬治疗的患者产生医学影响。
