干扰素α-利巴韦林联合疗法对慢性活动性丙型肝炎患者细胞色素P450 1A2、2D6及N-乙酰转移酶-2活性的影响

Effect of interferon alpha-ribavirin bitherapy on cytochrome P450 1A2 and 2D6 and N-acetyltransferase-2 activities in patients with chronic active hepatitis C.

作者信息

Becquemont Laurent, Chazouilleres Olivier, Serfaty Lawrence, Poirier Jean Marie, Broly Franck, Jaillon Patrice, Poupon Raoul, Funck-Brentano Christian

机构信息

Department of Pharmacology and the Clinical Investigation Center, Saint-Antoine University Hospital, Paris, France.

出版信息

Clin Pharmacol Ther. 2002 Jun;71(6):488-95. doi: 10.1067/mcp.2002.124468.

DOI:10.1067/mcp.2002.124468

PMID:12087352

Abstract

BACKGROUND

Interferon alpha (IFN-alpha) is thought to be responsible for cytochrome P450 (CYP)-dependent drug interactions mediated by a decrease in CYP activities.

OBJECTIVES

The objectives are to determine whether IFN-alpha and ribavirin can alter pretreatment CYP1A2, CYP2D6, CYP3A4 and N-acetyltransferase-2 activities after 1 month of treatment.

METHODS

Enzymatic activities were determined among 14 patients with chronic active hepatitis C before IFN-alpha (3. 10(6) U, 3 times a week) and ribavirin introduction and after 1 month of treatment. During both study periods, subjects received 80 mg dextromethorphan and 140 mg caffeine (1,3,7-trimethylxanthine [137X]). CYP3A4, CYP2D6, and NAT2 activities were assessed by use of urinary metabolic ratios of 3-methoxymorphinan/dextromethorphan, dextrorphan/dextromethorphan, and 5-acetylamino-6-formylamino-3-methyluracil (AFMU)/1-methylxanthine(1X). The plasma paraxanthine/caffeine ratio was used to measure CYP1A2 activity.

RESULTS

CYP3A4 and CYP2D6 activities tended to increase after 1 month of antiviral therapy, but the change did not reach statistical significance. CYP1A2 and NAT2 activities were not significantly modified after 1 month of antiviral treatment. Pretreatment activities were significantly lower than those previously observed in healthy volunteers for CYP2D6 (mean +/- SD, 148 +/- 139 versus 759 +/- 692; P =.0008) and CYP3A4 (0.18 +/- 0.06 versus 0.52 +/- 0.72; P =.0006). This difference was no longer statistically significant after 1 month of treatment, because CYP2D6 and CYP3A4 activities improved in 7 patients.

CONCLUSION

In patients with chronic hepatitis C, pretreatment CYP3A4 and CYP2D6 activities were significantly lower than those observed in healthy volunteers. These differences disappeared after 1 month of antiviral treatment because of the restoration of these CYP activities in about half of the patients.

摘要

背景

干扰素α（IFN-α）被认为是细胞色素P450（CYP）依赖性药物相互作用的原因，这种相互作用是由CYP活性降低介导的。

目的

目的是确定IFN-α和利巴韦林在治疗1个月后是否能改变治疗前CYP1A2、CYP2D6、CYP3A4和N-乙酰转移酶-2的活性。

方法

在14例慢性丙型肝炎患者中，于IFN-α（3.10⁶U，每周3次）和利巴韦林引入前以及治疗1个月后测定酶活性。在两个研究期间，受试者服用80mg右美沙芬和140mg咖啡因（1,3,7-三甲基黄嘌呤[137X]）。通过使用3-甲氧基吗啡烷/右美沙芬、右啡烷/右美沙芬和5-乙酰氨基-6-甲酰氨基-3-甲基尿嘧啶（AFMU）/1-甲基黄嘌呤（1X）的尿代谢比值评估CYP3A4、CYP2D6和NAT2的活性。血浆副黄嘌呤/咖啡因比值用于测量CYP1A2活性。

结果

抗病毒治疗1个月后，CYP3A4和CYP2D6活性有升高趋势，但变化未达到统计学意义。抗病毒治疗1个月后，CYP1A2和NAT2活性无明显改变。治疗前CYP2D6（均值±标准差，148±139对759±692；P = 0.0008）和CYP3A4（0.18±0.06对0.52±0.72；P = 0.0006）的活性显著低于先前在健康志愿者中观察到的活性。治疗1个月后，这种差异不再具有统计学意义，因为7例患者的CYP2D6和CYP3A4活性有所改善。