Burckart G J, Frye R F, Kelly P, Branch R A, Jain A, Fung J J, Starzl T E, Venkataramanan R
Department of Pharmaceutical Sciences, University of Pittsburgh, PA 15261, USA.
Clin Pharmacol Ther. 1998 Mar;63(3):296-302. doi: 10.1016/S0009-9236(98)90161-8.
To examine the phenotypic expression of CYP2E1 in liver transplant patients, as measured by the in vivo probe chlorzoxazone, and to evaluate CYP2E1 activity over time after transplantation.
Thirty-three stable liver transplant patients were given 250 mg chlorzoxazone within 1 year after transplantation as part of a multiprobe CYP cocktail; urine and blood were collected for 8 hours. Chlorzoxazone and 6-hydroxychlorzoxazone concentrations were determined by HPLC. Twenty-eight healthy control subjects, eight patients with moderate to severe liver disease, and four patients who had not received liver transplants were also studied for comparison. The chlorzoxazone metabolic ratio, calculated as the plasma concentration of 6-hydroxychlorzoxazone/chlorzoxazone at 4 hours after chlorzoxazone administration, was used as the phenotypic index. In a subgroup of patients and control subjects, additional blood samples were obtained to allow for the calculation of chlorzoxazone pharmacokinetic parameters by noncompartmental methods.
The chlorzoxazone metabolic ratio for the liver transplant patients in the first month after transplantation (mean +/- SD, 6.4 +/- 5.1) was significantly higher than that after 1 month after surgery (2.1 +/- 2.0), when the chlorzoxazone metabolic ratio was not different from control subjects (0.8 +/- 0.5). The chlorzoxazone metabolic ratios in the patients who had not received liver transplants (1.1 +/- 0.7) were equivalent to those of healthy control subjects. The maximum observed 6-hydroxychlorzoxazone plasma concentration was 3046 +/- 1848 ng/ml in seven liver transplant patients in the first month after surgery compared with 1618 +/- 320 ng/ml in 16 healthy control subjects (p < 0.05). The maximum observed concentration of chlorzoxazone, the chlorzoxazone apparent oral clearance, and the formation clearance of 6-hydroxychlorzoxazone were also significantly different between the groups.
We conclude that significant induction of CYP2E1, as indicated by the chlorzoxazone metabolic ratio, occurs in the first month after surgery in liver transplant patients and that drugs that are substrates for CYP2E1 may require dosage alteration during that period. Contrary to expectations, drug metabolism is not uniformly depressed after liver transplantation.
通过体内探针氯唑沙宗检测肝移植患者中CYP2E1的表型表达，并评估移植后不同时间的CYP2E1活性。
33例稳定的肝移植患者在移植后1年内服用250mg氯唑沙宗，作为多探针CYP鸡尾酒的一部分；收集8小时的尿液和血液。采用高效液相色谱法测定氯唑沙宗和6-羟基氯唑沙宗的浓度。还研究了28例健康对照者、8例中重度肝病患者和4例未接受肝移植的患者作为对照。氯唑沙宗代谢率以氯唑沙宗给药后4小时血浆中6-羟基氯唑沙宗/氯唑沙宗的浓度计算，作为表型指标。在患者和对照者的一个亚组中，采集额外的血样以便用非房室方法计算氯唑沙宗的药代动力学参数。
肝移植患者术后第一个月氯唑沙宗代谢率（均值±标准差，6.4±5.1）显著高于术后1个月（2.1±2.0），此时氯唑沙宗代谢率与对照者（0.8±0.5）无差异。未接受肝移植患者的氯唑沙宗代谢率（1.1±0.7）与健康对照者相当。术后第一个月，7例肝移植患者中观察到的6-羟基氯唑沙宗血浆最大浓度为3046±1848ng/ml，而16例健康对照者为1618±320ng/ml（p<0.05）。两组间氯唑沙宗的最大观察浓度、氯唑沙宗的表观口服清除率和6-羟基氯唑沙宗的生成清除率也有显著差异。
我们得出结论，肝移植患者术后第一个月出现氯唑沙宗代谢率所表明的CYP2E1显著诱导，在此期间CYP2E1底物药物可能需要调整剂量。与预期相反，肝移植后药物代谢并非均一性降低。
