Asghar Ali, Gorski J Christopher, Haehner-Daniels Barbara, Hall Stephen D
Division of Clinical Pharmacology, Indiana University School of Medicine, Wishard Memorial Hospital, 1001 West 10th Street, Indianapolis, IN 46202-2879, USA.
Drug Metab Dispos. 2002 Jan;30(1):20-6. doi: 10.1124/dmd.30.1.20.
Reverse transcription-polymerase chain reaction (RT-PCR) and quantitative, competitive RT-PCR were used to examine the capability of rifampin to induce the expression of mRNA derived from multidrug resistance-1 (MDR1) and drug-metabolizing cytochrome P450 (P450) genes in the mononuclear fraction (lymphocytes) of human blood. A total of 50 healthy volunteers (age, 18-74) participated in two studies in which 600 mg of rifampin was administered orally once daily in the evening for 7 days. Twenty of these individuals also received fexofenadine before and after rifampin dosing. MDR1 and CYP2C8 mRNAs were expressed in 100% (50 of 50) and 95% (35 of 37) of individuals, respectively, at baseline. A significant (P < 0.05; n = 37) increase in the expression of MDR1 mRNA from 176,900 +/- 122,000 to 248,500 +/- 162,300 molecules/microg of RNA was observed following rifampin administration in the human lymphocytes. There was no significant (P > 0.05) difference in MDR1 mRNA expression between males and females at baseline. Interestingly, 58% of the individuals (n = 29) demonstrated a 120% increase [95% confidence interval (CI); 120%; range, 81-153%; responders] in MDR1 mRNA expression. In contrast, the remaining 42% of individuals (n = 21) exhibited a mean decrease of -5.2% (95% CI; -5.2%; range, -15 to +4%; nonresponders). Rifampin steady-state trough serum concentrations were not significantly different (P > 0.05) between responders and nonresponders. Likewise, there was no relationship between the observed induction in MDR1 mRNA expression in lymphocytes and the observed increase in fexofenadine oral clearance in twenty volunteers. The mRNA of CYP2E1, CYP3A5, CYP3A7, CYP4A11, and CYP4B1 genes were variably expressed at baseline and following rifampin treatment. In contrast, CYP2C9 and CYP3A4 mRNAs were undetectable in lymphocytes both before and after rifampin dosing. Interindividual variability in baseline expression and inducibility of MDR1 and P450 mRNA in human lymphocytes appeared to be substantial and may not reflect the expression of these enzymes in other tissues.
采用逆转录聚合酶链反应（RT-PCR）和定量竞争性RT-PCR检测利福平诱导人血单核细胞（淋巴细胞）中多药耐药1（MDR1）和药物代谢细胞色素P450（P450）基因来源的mRNA表达的能力。共有50名健康志愿者（年龄18 - 74岁）参与了两项研究，其中600mg利福平于每晚口服1次，连续服用7天。这些个体中有20人在利福平给药前后还服用了非索非那定。基线时，MDR1和CYP2C8 mRNA分别在100%（50/50）和95%（35/37）的个体中表达。在人淋巴细胞中给予利福平后，观察到MDR1 mRNA表达从176,900±122,000分子/μg RNA显著增加（P<0.05；n = 37）至248,500±162,300分子/μg RNA。基线时男性和女性的MDR1 mRNA表达无显著差异（P>0.05）。有趣的是，58%的个体（n = 29）MDR1 mRNA表达增加了120%[95%置信区间（CI）；120%；范围，81 - 153%；反应者]。相比之下，其余42%的个体（n = 21）平均下降了 - 5.2%（95% CI； - 5.2%；范围， - 15至 + 4%；无反应者）。反应者和无反应者之间利福平稳态谷浓度无显著差异（P>0.0
