Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Eur J Clin Pharmacol. 2012 Apr;68(4):397-406. doi: 10.1007/s00228-011-1132-2. Epub 2011 Oct 18.
The basis of high intersubject variability of propofol metabolism is unclear. Therefore, we examined the influence of genetic polymorphisms of the key metabolizing enzymes cytochrome P450 2B6 (CYP2B6) and uridine diphosphate (UDP)-glucuronosyltransferase 1A9 (UGT1A9), age, and sex on propofol biotransformation in vitro and in vivo.
Plasma concentrations of propofol, 4-hydroxypropofol, and their glucuronides were measured over 20 min in 105 patients after a single intravenous bolus of propofol. Propofol 4-hydroxylation activity, genotypes, and content of CYP2B6 protein in 68 human livers were determined. The common single nucleotide polymorphisms (SNPs) for the CYP2B6 and UGT1A9 genes were analyzed by polymerase chain reaction (PCR).
Plasma levels of propofol metabolites showed high interindividual variability (range of coefficient of variation 89-128%). This was supported by in vitro data showing similar variability of propofol 4-hydroxylation in liver microsomes and 1.9-fold higher CYP2B6 protein content in the livers from women. No significant relationships were revealed between the SNPs studied and propofol metabolism. However, patients' sex had a pronounced effect on propofol metabolism. Thus, women had higher amounts of propofol glucuronide (1.25-fold; p = 0.03), 4-hydroxypropofol-1-glucuronide (2.1-fold; p = 0.0009), and 4-hydroxypropofol-4-glucuronide (1.7-fold; p = 0.02) as shown by the weight-corrected area under the time-plasma concentration curve of metabolites. Additionally, the sexual dimorphism in 4-hydroxypropofol glucuronidation was prominent in the 35- to 64-year-old subgroup.
No significant effects of CYP2B6 and UGT1A9 SNPs or age on propofol metabolism were revealed in this pilot study, but there was a pronounced effect of sex, a finding that indicates an important factor for the previously described sex difference in systemic clearance of propofol seen.
丙泊酚代谢的个体间高度变异性的基础尚不清楚。因此，我们研究了关键代谢酶细胞色素 P450 2B6（CYP2B6）和尿苷二磷酸（UDP）-葡萄糖醛酸基转移酶 1A9（UGT1A9）的遗传多态性、年龄和性别对体外和体内丙泊酚生物转化的影响。
在 105 例患者单次静脉推注丙泊酚后 20 分钟内，测量血浆中丙泊酚、4-羟基丙泊酚及其葡萄糖醛酸化物的浓度。测定 68 个人肝中丙泊酚 4-羟化活性、CYP2B6 蛋白的基因型和含量。通过聚合酶链反应（PCR）分析 CYP2B6 和 UGT1A9 基因的常见单核苷酸多态性（SNP）。
个体间丙泊酚代谢产物的血浆水平显示出高度的变异性（变异系数范围为 89-128%）。这一结果得到了体外数据的支持，即肝微粒体中丙泊酚 4-羟化的变异性相似，且女性肝中 CYP2B6 蛋白含量高出 1.9 倍。研究的 SNP 与丙泊酚代谢之间无显著相关性。然而，患者的性别对丙泊酚代谢有显著影响。因此，女性的丙泊酚葡萄糖醛酸化物（增加 1.25 倍；p=0.03）、4-羟基丙泊酚-1-葡萄糖醛酸化物（增加 2.1 倍；p=0.0009）和 4-羟基丙泊酚-4-葡萄糖醛酸化物（增加 1.7 倍；p=0.02）的量更高，这一点可从代谢物的时间-血浆浓度曲线下的重量校正面积看出。此外，在 35 至 64 岁的亚组中，4-羟基丙泊酚葡萄糖醛酸化的性别二态性尤为明显。
在这项初步研究中，CYP2B6 和 UGT1A9 SNP 或年龄对丙泊酚代谢无显著影响，但性别有显著影响，这一发现表明先前描述的丙泊酚全身清除率的性别差异的一个重要因素。
