Effects of Spice Constituents on P-Glycoprotein-Mediated Transport and CYP3A4-Mediated Metabolism in Vitro

Zhang, Wenxia; Lim, Lee Yong

doi:10.1124/dmd.107.019737

Cited by 89 publications

(77 citation statements)

References 33 publications

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“…It has been reported that activity of CYP3A4 enzyme is particularly sensitive to dietary effects [57]. Although the potential effect of food on sunitinib pharmacokinetics was not supported by the phase I study in healthy subjects, in which no difference of sunitinib and SU12662 pharmacokinetics was found between patients with single dose of sunitinib after either 10-hour fast or a high-fat meal, the effect of long-term cooking habit, such as the frequently used CYP3A4-inhibiting spices [58], could not be ignored.…”

Section: Discussionmentioning

confidence: 92%

Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis

et al. 2016

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Background: An increasing number of studies have reported ethnic differences in sunitinib outcome in metastatic renal cell carcinoma (mRCC) patients. However, a comprehensive analysis is still lacking. Therefore, we systematically collected available published data and performed a meta-analysis to compare sunitinib efficacy and toxicity in Asian and Caucasian mRCC patients. Methods: Data were extracted from published results from clinical trials, expanded access program and real-world clinical practice. Progression-free survival (or time to tumor progression), overall survival, objective response rate and adverse events were used as endpoints to evaluate the differences of sunitinib outcome between the two ethnicities. For adverse events, we focused the following clinically relevant side effects: diarrhea, fatigue, mucositis/stomatitis, hand-foot syndrome, hypertension, leukopenia, neutropenia and thrombocytopenia. Results: A total of 33 publications including 9977 patients were available for meta-analysis. The efficacy of sunitinib in Asian patients was similar to that in Caucasian patients. However, Asian patients showed a higher incidence of all grades toxicity of hand-foot syndrome, > grade 2 fatigue, > grade 2 hand-foot syndrome and > grade 2 thrombocytopenia. Conclusion: Ethnic differences in adverse events of sunitinib in mRCC patients existed and dose adjustment in Asian patients may be considered.

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Section: Discussionmentioning

confidence: 92%

Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis

et al. 2016

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“…[14][15][16][17] Apparently, the differential effect of PXT on MDZ metabolism is only able to be explaind using an atypical kinetics model. A hypothesis declared that CYP3A enzyme contains two or more MDZ-binding sites.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Action of Panaxytriol on Midazolam 1′-Hydroxylation and 4-Hydroxylation Mediated by CYP3A in Liver Microsomes and Rat Primary Hepatocytes

Zhang

Zeng

et al. 2015

Biological & Pharmaceutical Bulletin

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In our previous study, panaxytriol (PXT) was shown to enhance midazolam (MDZ) 1′-hydroxylation significantly but to inhibit MDZ 4-hydroxylation. To explore the underlying mechanism, we investigated the effects of PXT on cytochrome P450 3A (CYP3A)-mediated MDZ metabolic pathways using rat liver microsomes (RLM), human liver microsomes (HLM), and rat primary hepatocytes. In the presence of PXT, the V max of 4-OH MDZ decreased from 0.72 to 0.51 nmol/min·mg pro in RLM and from 0.32 to 0.12 nmol/ min·mg pro in HLM, and the K m value increased from 5.12 to 7.26 µM in RLM and from 27.87 to 32.80 µM in HLM. But the presence of PXT reduced the K m and increased the V max values of MDZ 1′-hydroxylation in RLM and HLM. Interestingly, the differential effect of PXT on MDZ 4-hydroxylation and 1′-hydroxylation was also observed in primary rat hepatocytes after 45-min culture. PXT did not affect the expression levels of CYP3A1/2 mRNA in rat hepatocytes. With extension of the culture time to 6 h, however, PXT significantly inhibited both MDZ 4-hydroxylation and 1′-hydroxylation, and the expression level of CYP3A1/2 mRNA was decreased to 87% and 80% (CYP3A1) and to 89% and 85% (CYP3A2) of those in controls in the presence of PXT 4.0 and 8.0 µg/mL, respectively. These results suggest that PXT could activate MDZ 1′-hydroxylation but inhibit MDZ 4-hydroxylation by changing the CYP3A enzyme affinity and metabolic rate after a shortterm intervention. However, long-term treatment with PXT could inhibit both the 4-hydroxylation and 1′-hydroxylation of MDZ by downregulating CYP3A1/2 mRNA expression.Key words panaxytriol; midazolam hydroxylation metabolism; cytochrome P450 3A; differential effect mechanism Cytochrome P450 (CYP450) is a superfamily of hemeproteins that involved in the biotransformation of the majority of clinical drugs. The inhibition or induction effect of clinical drugs on CYP450 is considered as one of the important factors leading to potential drug-drug interactions.1-3) CYP3A4 is one of the primary CYP450 enzymes in human liver and catalyzes the metabolism of more than 50% of clinical drugs including terfenadine, theophylline and astemizole, etc. Midazolam (MDZ) is the specific substrate of CYP3A4 enzyme and is mainly metabolized to 4-hydroxymidazolam (4-OH MDZ) and 1′-hydroxymidazolam (1′-OH MDZ) by combining with the two different sites of CYP3A4 enzyme active center.4,5) Therefore, the formation of the two metabolites are often simultaneously quantified for the assessment of CYP3A4 activity.Traditional Chinese medicine is widely used in clinical practice in China because of the advantages of good curative effect and less adverse reaction. The incidence of Chinese medicine and chemical medicine interactions significantly increased as the widely using of Chinese medicine, and the change of CYP450 enzyme activity is the principal cause resulting in drug metabolic interactions. 6,7) As a well known study, salvia extract exhibited a marked inhibition effect on the expression of CYP3A4 and CYP1A2 mRNA in HepG2, and high...

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“…Recent advances have demonstrated that CYP3A4 cooperativity involves the binding of multiple (at least 2) substrate molecules to the binding pocket and represents a case of true allostery characterized by effector-induced conformational transitions (Davydov and Halpert, 2008). On the basis of the above theory and our results, the differential effects of PXT on the metabolism of MDZ, similar to the effectors of citral, 6-gingerol, and D-limonene (Zhang and Lim, 2008), can be explained by a two-site model (Korzekwa et al, 1998;Domanski et al, 2001) or a multi-site model (Kenworthy et al, 2001;Manoj et al, 2010;Smirnov et al, 2011) of CYP3A4. It can be hypothesized that PXT can bind to one defined site that is also occupied by MDZ in the position required for 4-hydroxylation (or 19-hydroxylation) and that both substrates can displace each other.…”

Section: Discussionmentioning

confidence: 78%

“…Drug interactions involving substrates, inhibitors, activators, or inducers of CYP3A4 are more prevalent and complex than those of other members of the P450 family (Kim et al, 2006;Pal and Mitra, 2006). It is becoming evident that many CYP3A4-mediated reactions proceed with atypical MichaelisMenten kinetics, including substrate activation (Shou et al, 1999), substrate inhibition (Lin et al, 2001;Wu, 2011), and differential kinetics Zhang and Lim, 2008;Xia et al, 2009). These phenomena are thought to be due to the binding of multiple substrates within the active site of the enzyme (Kenworthy et al, 2001;Galetin et al, 2003;Zhou et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Identification of the Active Components in Shenmai Injection that Differentially Affect Cyp3a4-Mediated 1′-Hydroxylation and 4-Hydroxylation of Midazolam

Zeng

Xia

et al. 2013

Drug Metab Dispos

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Shenmai injection (SMI) is a popular herbal preparation that is widely used for the treatment of atherosclerotic coronary heart disease and viral myocarditis. In our previous study, SMI was shown to differentially affect CYP3A4-mediated 19-hydroxylation and 4-hydroxylation of midazolam (MDZ). The present study was conducted to identify the active components in SMI responsible for the differential effects on MDZ metabolism, using in vitro incubation systems (rat and human liver microsomes and a recombinant CYP3A4 system) to measure 19-hydroxylation and 4-hydroxylation of MDZ. First, different fractions of SMI were obtained by gradient elution on an solid phase extraction system and individually tested for their effects on MDZ metabolism. The results demonstrated that lipid-soluble constituents were likely to be the predominant active components of SMI. Second, the possible active components were gradually separated on an high-performance liquid chromatography system under different conditions and individually tested in vitro for their effects on MDZ metabolism. Third, the active component obtained in the above experiment was collected and subjected to structural analysis, and identified as panaxytriol (PXT). Finally, it was validated that PXT had significant differential effects on 19-hydroxylation and 4-hydroxylation of MDZ in various in vitro systems that were similar to those of SMI. We conclude that PXT is the constituent of SMI responsible for the differential effects on CYP3A4-mediated 19-hydroxylation and 4-hydroxylation of MDZ.

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Effects of Spice Constituents on P-Glycoprotein-Mediated Transport and CYP3A4-Mediated Metabolism in Vitro

Abstract: ABSTRACT:The effects of eight components from six commonly consumed spices on P-glycoprotein (P-gp) transport and CYP3A4 metabolism were evaluated in vitro. P-gp-mediated

Cited by 89 publications

References 33 publications

Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis

Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis

Mechanism of Action of Panaxytriol on Midazolam 1′-Hydroxylation and 4-Hydroxylation Mediated by CYP3A in Liver Microsomes and Rat Primary Hepatocytes

Identification of the Active Components in Shenmai Injection that Differentially Affect Cyp3a4-Mediated 1′-Hydroxylation and 4-Hydroxylation of Midazolam

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