Chatterjee Parnali, Franklin Michael R
Department of Pharmacology & Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT 84112-5820, USA.
Drug Metab Dispos. 2003 Nov;31(11):1391-7. doi: 10.1124/dmd.31.11.1391.
The concurrent use of herbal medicinals with prescription and over-the-counter drugs carries a risk for unanticipated adverse drug-botanical pharmacokinetic interactions, particularly as a result of cytochrome P450 (P450) inhibition. Extracts of goldenseal (Hydrastis canadensis) containing approximately equal concentrations ( approximately 17 mM) of two methylenedioxyphenyl alkaloids, berberine and hydrastine, inhibited with increasing potency (CYP2C9) diclofenac 4'-hydroxylation, (CYP2D6) bufuralol 1'-hydroxylation, and (CYP3A4) testosterone 6beta-hydroxylation activities in human hepatic microsomes. The inhibition of testosterone 6beta-hydroxylation activity was noncompetitive with an apparent Ki of 0.11% extract. Of the methylenedioxyphenyl alkaloids, berberine (IC50 = 45 microM) was the more inhibitory toward bufuralol 1'-hydroxylation and hydrastine (IC50 approximately 350 microM for both isomers), toward diclofenac 4'-hydroxylation. For testosterone 6beta-hydroxylation, berberine was the least inhibitory component (IC50 approximately 400 microM). Hydrastine inhibited testosterone 6beta-hydroxylation with IC50 values for the (+)- and (-)-isomers of 25 and 30 microM, respectively. For (-)-hydrastine, an apparent Ki value of 18 microM without preincubation and an NADPH-dependent mechanism-based inhibition with a kinactivation of 0.23 min(-1) and a KI of approximately 110 microM were determined. Cytochrome P450 metabolic-intermediate (MI) complex formation could be demonstrated for both hydrastine isomers. With expressed P450 isoforms, hydrastine formed a P450 MI complex with CYP2C9, CYP2D6, and CYP3A4. Coexpression of cytochrome b5 with the P450 isoforms enhanced the rate but not the extent of P450 MI complex formation.
草药与处方药和非处方药同时使用会带来意外的不良药物 - 植物药药代动力学相互作用的风险，尤其是由于细胞色素P450（P450）抑制作用。含有两种亚甲二氧基苯基生物碱（小檗碱和白毛茛碱）近似相等浓度（约17 mM）的白毛茛（Hydrastis canadensis）提取物，在人肝微粒体中对双氯芬酸4'-羟化（CYP2C9）、布非洛尔1'-羟化（CYP2D6）和睾酮6β-羟化（CYP3A4）活性的抑制作用随效力增加。睾酮6β-羟化活性的抑制是非竞争性的，提取物的表观Ki为0.11%。在亚甲二氧基苯基生物碱中，小檗碱（IC50 = 45 microM）对布非洛尔1'-羟化的抑制作用更强，而白毛茛碱（两种异构体的IC50约为350 microM）对双氯芬酸4'-羟化的抑制作用更强。对于睾酮6β-羟化，小檗碱是抑制作用最小的成分（IC50约为400 microM）。白毛茛碱抑制睾酮6β-羟化，（+）-和（-）-异构体的IC50值分别为25和30 microM。对于（-）-白毛茛碱，未预温育时的表观Ki值为18 microM，基于NADPH的机制性抑制作用的失活速率常数为0.23 min(-1)，KI约为110 microM。两种白毛茛碱异构体均可证明细胞色素P450代谢中间体（MI）复合物的形成。对于表达的P450同工酶，白毛茛碱与CYP2C9、CYP2D6和CYP3A4形成P450 MI复合物。细胞色素b5与P450同工酶的共表达提高了P450 MI复合物形成的速率，但没有提高其程度。
