Diczfalusy Ulf, Kanebratt Kajsa P, Bredberg Eva, Andersson Tommy B, Böttiger Ylva, Bertilsson Leif
Division of Clinical Chemistry, Department of Laboratory Medicine at Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Br J Clin Pharmacol. 2009 Jan;67(1):38-43. doi: 10.1111/j.1365-2125.2008.03309.x. Epub 2008 Nov 6.
The oxysterol 4beta-hydroxycholesterol has been suggested as a marker for CYP3A4/5 activity. We have previously shown that plasma 4beta-hydroxycholesterol continues to increase for several weeks after maximal induction of CYP3A4/5 by carbamazepine at the dose given. In the present study we aimed to determine the time course of the decrease in plasma 4beta-hydroxycholesterol after termination of induction of CYP3A4/5 by rifampicin. An additional aim was to determine the variation in plasma level of 4beta-hydroxycholesterol with time in 12 untreated healthy volunteers.
Twenty-four healthy subjects were allocated into three study groups of equal sizes. The volunteers were treated with rifampicin (either 20 mg day(-1), 100 mg day(-1) or 500 mg day(-1)) for 2 weeks. Blood samples were taken before, during and after rifampicin treatment. In another group of 12 untreated volunteers blood samples were collected at different time points in order to determine the intraindividual variations in plasma 4beta-hydroxycholesterol concentrations. Plasma levels of 4beta-hydroxycholesterol were determined by isotope-dilution gas chromatography-mass spectrometry.
Rifampicin treatment increased plasma 4beta-hydroxycholesterol levels. After termination of rifampicin treatment plasma levels of 4beta-hydroxycholesterol decreased slowly with an apparent half-life of 17 days. The intraindividual variation in plasma levels of 4beta-hydroxycholesterol in untreated subjects was low, with coefficients of variation of between 4.8 and 13.2% over a period of 3 months.
After termination of induction of CYP3A4/5, plasma 4beta-hydroxycholesterol levels decreased slowly during 8 weeks. The half-life of elimination (17 days) resembled that of cholesterol rather than other oxysterols. The long half-life results in stable plasma concentrations with time.
氧化甾醇4β-羟基胆固醇被认为是CYP3A4/5活性的标志物。我们之前已经表明，在给予卡马西平以最大剂量诱导CYP3A4/5后，血浆4β-羟基胆固醇会持续升高数周。在本研究中，我们旨在确定利福平诱导CYP3A4/5终止后血浆4β-羟基胆固醇下降的时间进程。另一个目的是确定12名未经治疗的健康志愿者血浆中4β-羟基胆固醇水平随时间的变化情况。
24名健康受试者被平均分为三个研究组。志愿者接受利福平（20毫克/天、100毫克/天或500毫克/天）治疗2周。在利福平治疗前、治疗期间和治疗后采集血样。在另一组12名未经治疗的志愿者中，在不同时间点采集血样，以确定血浆4β-羟基胆固醇浓度的个体内差异。通过同位素稀释气相色谱-质谱法测定血浆4β-羟基胆固醇水平。
利福平治疗可提高血浆4β-羟基胆固醇水平。利福平治疗终止后，血浆4β-羟基胆固醇水平缓慢下降，表观半衰期为17天。未经治疗的受试者血浆4β-羟基胆固醇水平的个体内差异较低，在3个月的时间内变异系数在4.8%至13.2%之间。
CYP3A4/5诱导终止后，血浆4β-羟基胆固醇水平在8周内缓慢下降。消除半衰期（17天）与胆固醇相似，而非其他氧化甾醇。较长的半衰期导致血浆浓度随时间稳定。
