McCune J S, Hawke R L, LeCluyse E L, Gillenwater H H, Hamilton G, Ritchie J, Lindley C
University of North Carolina, Chapel Hill 27599-7360, USA.
Clin Pharmacol Ther. 2000 Oct;68(4):356-66. doi: 10.1067/mcp.2000.110215.
The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers; and the concentration-effect relationship between dexamethasone and CYP3A4 activity in primary human hepatocyte cultures.
The effect of dexamethasone (8 mg administered by mouth two times a day for 5 days) on CYP3A4 activity in 12 healthy volunteers was assessed with the erythromycin breath test and urinary ratio of dextromethorphan to 3-methoxymorphinan. Concentration-effect of dexamethasone on CYP3A4-dependent testosterone 6-beta-hydroxylation was determined in human hepatocytes treated with 2 to 250 micromol/L dexamethasone.
The percent of erythromycin metabolized per hour increased from 2.20% +/- 0.60% (mean +/- SD) at baseline to 2.67% +/- 0.55% on day 5 of dexamethasone (mean increase in hepatic CYP3A4 activity 25.7% +/- 24.6%; P = .004). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 28 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (mean decrease = 49%; P = .06). Substantial intersubject variability was observed in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r2 = 0.58). In hepatocytes, dexamethasone 2 to 250 micromol/L resulted in an average 1.7-fold to 6.9-fold increase in CYP3A4 activity, respectively. The extent of CYP3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r2 = 0.59).
These data demonstrate that dexamethasone at doses used clinically increased CYP3A4 activity with extensive intersubject variability and that the extent of CYP3A4 induction was, in part, predicted by the baseline activity of CYP3A4 in both healthy volunteers and human hepatocyte cultures.
这些实验的目的是确定地塞米松治疗方案对健康志愿者细胞色素P4503A4（CYP3A4）活性的影响；以及地塞米松与原代人肝细胞培养物中CYP3A4活性之间的浓度-效应关系。
通过红霉素呼气试验和右美沙芬与3-甲氧基吗啡喃的尿排泄率评估地塞米松（每天口服8mg，共5天）对12名健康志愿者CYP3A4活性的影响。用2至250μmol/L地塞米松处理人肝细胞，测定地塞米松对CYP3A4依赖性睾酮6-β-羟化的浓度-效应。
每小时代谢的红霉素百分比从基线时的2.20%±0.60%（平均值±标准差）增加到地塞米松治疗第5天时的2.67%±0.55%（肝脏CYP3A4活性平均增加25.7%±24.6%；P = 0.004）。基线时和地塞米松治疗第5天时，右美沙芬与3-甲氧基吗啡喃的平均尿排泄率分别为28（4.8至109）和7（1至23）（平均下降 = 49%；P = 0.06）。观察到CYP3A4诱导程度存在显著的个体间差异。CYP3A4诱导程度与基线红霉素呼气试验呈负相关（r2 = 0.58）。在肝细胞中，2至250μmol/L地塞米松分别使CYP3A4活性平均增加1.7倍至6.9倍。地塞米松在肝细胞制剂中诱导CYP3A4的程度与基线活性呈负相关（r2 = 0.59）。
这些数据表明，临床使用剂量的地塞米松可增加CYP3A4活性，且个体间差异较大，在健康志愿者和人肝细胞培养物中，CYP3A4诱导程度部分可由CYP3A4的基线活性预测。
