Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
Br J Clin Pharmacol. 2013 Feb;75(2):450-62. doi: 10.1111/j.1365-2125.2012.04364.x.
Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers.
A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing.
Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma C(max), AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05-0.08 μM and 0.6 μM, respectively).
The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes.
姜黄提取物中的姜黄素类（姜黄素、脱甲氧基姜黄素和双脱甲氧基姜黄素）目前正在被评估用于治疗癌症和阿尔茨海默病。先前的体外研究表明，姜黄素类和胡椒碱（一种可增强姜黄素生物利用度的黑胡椒衍生物）可能抑制人细胞色素 P450（CYP）3A、CYP2C9、尿苷二磷酸葡萄糖醛酸转移酶（UGT）和磺基转移酶（SULT）依赖性药物代谢。本研究旨在确定市售姜黄素/胡椒碱提取物是否会改变这些酶的探针药物在人体志愿者中的药代动力学分布。
在 8 名健康志愿者中进行了一项随机、安慰剂对照、六向交叉研究。在 2 天内口服 4 次标准化的姜黄素/胡椒碱制剂（4 g 姜黄素类加 24 mg 胡椒碱）或匹配的安慰剂，然后口服咪达唑仑（CYP3A 探针）、氟比洛芬（CYP2C9 探针）或对乙酰氨基酚（扑热息痛）（双重 UGT 和 SULT 探针）。采用高效液相色谱法测定药物、代谢物和草药在血浆和尿液中的浓度。咪达唑仑给药后还测量了受试者的镇静和脑电图效应。
与安慰剂相比，姜黄素/胡椒碱处理对咪达唑仑、氟比洛芬或对乙酰氨基酚的血浆 Cmax、AUC、清除率、消除半衰期或代谢物水平没有产生有意义的影响（α=0.05，配对 t 检验）。姜黄素/胡椒碱处理对咪达唑仑的药效学也没有影响。尽管在使用葡萄糖醛酸酶/硫酸酯酶处理后，血浆中很容易检测到姜黄素类和胡椒碱的浓度，但未结合的浓度始终低于检测阈值（分别为 0.05-0.08 μM 和 0.6 μM）。
结果表明，短期使用这种胡椒碱增强的姜黄素制剂不太可能导致涉及 CYP3A、CYP2C9 或对乙酰氨基酚结合酶的临床显著相互作用。
