RESUMO
The interaction potential of Cynara scolymus L., Mikania glomerata Spreng.,Rhamnus purshiana DC and Uncaria tomentosa (Willd. Ex Roem. & Schult.) with conventional drugs metabolized by the CYP3A4 metabolic route was tested in HeLa cell lines, using the in vitro model of the hPXR. The herbal medicines C. scolymus (1.5 mg/mL dry extract) did not affect the receptor. On the other hand, M. glomerata (5.5 mg/mL dry extract), R. purshiana (1.5 mg/mL dry extract), and U. tomentosa (2.0 mg/mL dry extract) showed to be hPXR agonist, suggesting a potential interaction with the conventional drugs metabolized by the same isoforms of the CYP superfamily. The results from this study contribute to the use safer and more effective of these herbal medicines.
Se evaluó el potencial de interacción de Cynara scolymus L., Mikania glomerata Spreng., Rhamnus purshiana DC y Uncaria tomentosa (Willd. Ex Roem. & Schult.) con fármacos convencionales metabolizados por la ruta metabólica CYP3A4 en líneas celulares HeLa, utilizando el modelo in vitro del hPXR. Las hierbas medicinales C. scolymus (1,5 mg/mL de extracto seco) no afectaron al receptor. Por otro lado, M. glomerata (5.5 mg/mL de extracto seco), R. purshiana (1.5 mg/mL de extracto seco) y U. tomentosa (2.0 mg/mL de extracto seco) mostraron ser agonistas de hPXR, lo que sugiere una potencial interacción con los fármacos convencionales metabolizados por las mismas isoformas de la superfamilia CYP. Los resultados de este estudio contribuyen a un uso más seguro y eficaz de estos medicamentos a base de hierbas medicinales.
Assuntos
Rhamnus , Unha-de-Gato , Cynara scolymus , Mikania , Interações Ervas-Drogas , Plantas Medicinais , Técnicas In Vitro , Indutores do Citocromo P-450 CYP3A/químicaRESUMO
BACKGROUND: Praziquantel (PZQ), which possesses an asymmetric center, is classified as a pyrazinoisoquinoline and has been the mainstay in the treatment of schistosomiasis since 1980. PZQ undergoes a pronounced first-pass metabolism in the liver through the CYP450 system which could be mediated by nuclear receptors. OBJECTIVE: The purpose of this study was to investigate the possible different induction effects of CYP3A4 by PZQ racemate and enantiomers via the pregnane X receptor (PXR) and the effect of PXR polymorphism on the induction potency of PZQs. METHODS: The dual-luciferase reporter gene systems constructed in HepG2 cells were used to measure the abilities of PZQs to induce CYP3A4 expression mediated by PXR. The mRNA and protein levels of CYP3A4 were evaluated by polymerase chain reaction (PCR) and western blotting, respectively. RESULTS: In HepG2 cells transfected with PXRwt, PXR158, PXR163, PXR370 or PXR403 expression plasmids, PZQ racemate and its enantiomers up-regulated the luciferase activity in a concentration-dependent manner, while reaching saturation after transfected with PXR379 expression plasmids. The mRNA and protein expression of CYP3A4 was effectively activated in PXR-transfected HepG2 cells. The induction ability of CYP3A4 mediated by PXR activation by PZQ racemate and its enantiomers were statistically different between the same PXR group and different PXR groups. CONCLUSION: The enantioselective induction effects of PZQs on CYP3A4 were related to the enantioselective activations of PXR by PZQs and were influenced by the PXR gene polymorphism. These findings provide a basis for further understanding the enantiomeric metabolism and the variable efficacy of PZQs.
Assuntos
Indutores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Praziquantel/farmacologia , Receptor de Pregnano X/metabolismo , Indutores do Citocromo P-450 CYP3A/química , Células Hep G2 , Humanos , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Praziquantel/química , Receptor de Pregnano X/genética , EstereoisomerismoRESUMO
Cytochrome P450 46A1 (CYP46A1) or cholesterol-24-hydroxylase is responsible for cholesterol metabolism and homeostasis in the human brain. More recently its activity has been linked to brain function and disease. The anti-HIV drug efavirenz activates CYP46A1 at low drug levels while inhibiting the enzyme activity at the high dose used in clinical practice. Synthetic analogs and hydroxylated metabolites of efavirenz enhance CYP46A1 activity, with reduced unwanted enzyme inhibition at higher concentrations. These observations provide a platform for structural modifications of efavirenz to modulate CYP46A1 activity as a therapeutic target of brain disorders such as Alzheimer's disease, for which currently no treatment is available.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzoxazinas/uso terapêutico , Encéfalo/efeitos dos fármacos , Colesterol 24-Hidroxilase/metabolismo , Indutores do Citocromo P-450 CYP3A/uso terapêutico , Alcinos , Doença de Alzheimer/patologia , Animais , Benzoxazinas/química , Colesterol 24-Hidroxilase/química , Ciclopropanos , Indutores do Citocromo P-450 CYP3A/química , HumanosRESUMO
Cytochrome P450 46A1 (CYP46A1) is a central nervous system-specific enzyme, which catalyzes cholesterol 24-hydroxylation. Currently CYP46A1 is being evaluated in a clinical trial for activation by small doses of the anti-HIV drug efavirenz. Eight efavirenz-related compounds were investigated for CYP46A1 activation in vitro, induction of a CYP46A1 spectral response, spectral Kd values, interaction with the P450 allosteric sites, and a model of binding to the enzyme active site. We gained insight into structure-activity relationships of efavirenz for CYP46A1 activation and found that the investigated efavirenz primary metabolites are stronger and better activators of CYP46A1 than efavirenz. We also established that CYP46A1 is activated by racemates and that a conformational-selection mechanism is operative in CYP46A1. The results suggest structural modifications of efavirenz to further increase CYP46A1 activation without inhibition at high compound concentrations. It is possible that not only efavirenz but its metabolites activate CYP46A1 in vivo.
Assuntos
Benzoxazinas/química , Benzoxazinas/farmacologia , Colesterol 24-Hidroxilase/metabolismo , Indutores do Citocromo P-450 CYP3A/química , Indutores do Citocromo P-450 CYP3A/farmacologia , Preparações Farmacêuticas/metabolismo , Alcinos , Sítio Alostérico , Domínio Catalítico , Colesterol/metabolismo , Colesterol 24-Hidroxilase/química , Ciclopropanos , Humanos , Hidroxilação , Técnicas In Vitro , Preparações Farmacêuticas/química , Conformação ProteicaRESUMO
Described herein is a new approach to mitigate CYP3A4 induction. In this unconventional approach, a fine-tuning of the dihedral angle between the C4 phenyl and the dihydropyrimidine core of the heteroaryldihydropyrimidine (HAP) class of capsid inhibitors successfully altered the structure-activity-relationships (SARs) of the unwanted CYP3A4 induction and the desired HBV capsid inhibition to more favorable values. This eventually led to the discovery of a new capsid inhibitor with significantly reduced CYP3A4 induction, excellent anti-HBV activity, favorable preclinical PK/PD profiles, and no early safety flags.
Assuntos
Antivirais/farmacologia , Capsídeo/efeitos dos fármacos , Indutores do Citocromo P-450 CYP3A/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Receptor de Pregnano X/metabolismo , Animais , Antivirais/química , Antivirais/farmacocinética , Cristalografia por Raios X , Indutores do Citocromo P-450 CYP1A2/química , Indutores do Citocromo P-450 CYP1A2/farmacologia , Indutores do Citocromo P-450 CYP2B6/química , Indutores do Citocromo P-450 CYP2B6/farmacologia , Citocromo P-450 CYP3A/química , Indutores do Citocromo P-450 CYP3A/química , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Camundongos Endogâmicos BALB C , Ratos , Relação Estrutura-AtividadeRESUMO
The P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types, especially those involved in inflammatory and immune processes. High-throughput screening led to a new class of P2X4 inhibitors with substantial CYP 3A4 induction in human hepatocytes. A structure-guided optimization with respect to decreased pregnane X receptor (PXR) binding was started. It was found that the introduction of larger and more polar substituents on the ether linker led to less PXR binding while maintaining the P2X4 inhibitory potency. This translated into significantly reduced CYP 3A4 induction for compounds 71 and 73. Unfortunately, the in vivo pharmacokinetic (PK) profiles of these compounds were insufficient for the desired profile in humans. However, BAY-1797 (10) was identified and characterized as a potent and selective P2X4 antagonist. This compound is suitable for in vivo studies in rodents, and the anti-inflammatory and anti-nociceptive effects of BAY-1797 were demonstrated in a mouse complete Freund's adjuvant (CFA) inflammatory pain model.
Assuntos
Acetamidas/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Descoberta de Drogas , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X4/química , Acetamidas/química , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Indutores do Citocromo P-450 CYP3A/química , Indução Enzimática , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Inflamação/patologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/metabolismo , Dor/patologia , Antagonistas do Receptor Purinérgico P2X/química , Ratos , Ratos WistarRESUMO
We report physiologically based pharmacokinetic-modeling analyses to determine olaparib (tablet or capsule) drug-drug interactions (DDIs). Verified DDI simulations provided dose recommendations for olaparib coadministration with clinically relevant CYP3A4 modulators to eliminate potential risk to patient safety or olaparib efficacy. When olaparib is given with strong/moderate CYP3A inhibitors, the dose should be reduced to 100/150 mg b.i.d. (tablet), and 150/200 mg b.i.d. (capsule). Olaparib administration is not recommended with strong/moderate CYP3A inducers. No dose reductions are required with weak CYP3A inhibitors/inducers. Olaparib was shown to be a weak inhibitor of CYP3A (1.6-fold increase in exposure of a sensitive CYP3A probe) and to have no effect on P-glycoprotein or UGT1A1 substrates. Finally, this model was used to simulate exposure in scenarios where clinical data of olaparib are lacking, such as severe renal or hepatic impairment populations, and provided initial dosing recommendations in pediatric patients.
Assuntos
Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Modelos Biológicos , Ftalazinas/farmacocinética , Piperazinas/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Indutores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/química , Relação Dose-Resposta a Droga , Composição de Medicamentos , Interações Medicamentosas/fisiologia , Humanos , Ftalazinas/química , Piperazinas/química , Inibidores de Poli(ADP-Ribose) Polimerases/químicaRESUMO
Drug-drug interactions (DDIs) via cytochrome P450 (P450) induction are one clinical problem leading to increased risk of adverse effects and the need for dosage adjustments and additional therapeutic monitoring. In silico models for predicting P450 induction are useful for avoiding DDI risk. In this study, we have established regression models for CYP3A4 and CYP2B6 induction in human hepatocytes using several physicochemical parameters for a set of azole compounds with different P450 induction as characteristics as model compounds. To obtain a well-correlated regression model, the compounds for CYP3A4 or CYP2B6 induction were independently selected from the tested azole compounds using principal component analysis with fold-induction data. Both of the multiple linear regression models obtained for CYP3A4 and CYP2B6 induction are represented by different sets of physicochemical parameters. The adjusted coefficients of determination for these models were of 0.8 and 0.9, respectively. The fold-induction of the validation compounds, another set of 12 azole-containing compounds, were predicted within twofold limits for both CYP3A4 and CYP2B6. The concordance for the prediction of CYP3A4 induction was 87% with another validation set, 23 marketed drugs. However, the prediction of CYP2B6 induction tended to be overestimated for these marketed drugs. The regression models show that lipophilicity mostly contributes to CYP3A4 induction, whereas not only the lipophilicity but also the molecular polarity is important for CYP2B6 induction. Our regression models, especially that for CYP3A4 induction, might provide useful methods to avoid potent CYP3A4 or CYP2B6 inducers during the lead optimization stage without performing induction assays in human hepatocytes.
Assuntos
Azóis/farmacologia , Simulação por Computador , Indutores do Citocromo P-450 CYP2B6/farmacologia , Citocromo P-450 CYP2B6/biossíntese , Indutores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/biossíntese , Hepatócitos/efeitos dos fármacos , Modelos Estatísticos , Adulto , Azóis/química , Azóis/toxicidade , Células Cultivadas , Citocromo P-450 CYP2B6/genética , Indutores do Citocromo P-450 CYP2B6/química , Indutores do Citocromo P-450 CYP2B6/toxicidade , Citocromo P-450 CYP3A/genética , Indutores do Citocromo P-450 CYP3A/química , Indutores do Citocromo P-450 CYP3A/toxicidade , Interações Medicamentosas , Hepatócitos/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Análise de Componente Principal , RNA Mensageiro/biossíntese , Análise de Regressão , Relação Estrutura-Atividade , Fatores de TempoRESUMO
We report here a novel series of benzimidazole sulfonamides that act as antagonists of the S1P1 receptor, identified by exploiting an understanding of the pharmacophore of a high throughput screening (HTS)-derived series of compounds described previously. Lead compound 2 potently inhibits S1P-induced receptor internalization in a cell-based assay (EC50 = 0.05 µM), but has poor physical properties and metabolic stability. Evolution of this compound through structure-activity relationship development and property optimization led to in vivo probes such as 4. However, this compound was unexpectedly found to be a potent CYP3A inducer in human hepatocytes, and thus further chemistry efforts were directed at addressing this liability. By employing a pregnane X receptor (PXR) reporter gene assay to prioritize compounds for further testing in human hepatocytes, we identified lipophilicity as a key molecular property influencing the likelihood of P450 induction. Ultimately, we have identified compounds such as 46 and 47, which demonstrate the desired S1P1 antagonist activity while having greatly reduced risk of CYP3A induction in humans. These compounds have excellent oral bioavailability in preclinical species and exhibit pharmacodynamic effects of S1P1 antagonism in several in vivo models following oral dosing. Relatively modest antitumor activity was observed in multiple xenograft models, however, suggesting that selective S1P1 antagonists would have limited utility as anticancer therapeutics as single agents.
Assuntos
Benzimidazóis/química , Piridinas/química , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Sulfonamidas/química , Administração Oral , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Disponibilidade Biológica , Células Cultivadas , Citocromo P-450 CYP3A/biossíntese , Indutores do Citocromo P-450 CYP3A/síntese química , Indutores do Citocromo P-450 CYP3A/química , Indutores do Citocromo P-450 CYP3A/farmacologia , Genes Reporter , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Receptor de Pregnano X , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Esteroides/genética , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The pregnane X receptor [PXR (NR1I2)] induces the expression of xenobiotic metabolic genes and transporter genes. In this study, we aimed to establish a computational method for quantifying the enzyme-inducing potencies of different compounds via their ability to activate PXR, for the application in drug discovery and development. To achieve this purpose, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) for predicting enzyme-inducing potencies, based on computer-ligand docking to multiple PXR protein structures sampled from the trajectory of a molecular dynamics simulation. Molecular mechanics-generalized born/surface area scores representing the ligand-protein-binding free energies were calculated for each ligand. As a result, the predicted enzyme-inducing potencies for compounds generated by the CoMFA model were in good agreement with the experimental values. Finally, we concluded that this 3D-QSAR model has the potential to predict the enzyme-inducing potencies of novel compounds with high precision and therefore has valuable applications in the early stages of the drug discovery process.
Assuntos
Indutores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Descoberta de Drogas/métodos , Hepatócitos/efeitos dos fármacos , Modelos Moleculares , Receptores de Esteroides/agonistas , Inteligência Artificial , Citocromo P-450 CYP3A/genética , Indutores do Citocromo P-450 CYP3A/química , Indutores do Citocromo P-450 CYP3A/metabolismo , Bases de Dados de Proteínas , Transferência de Energia , Indução Enzimática/efeitos dos fármacos , Sistemas Inteligentes , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Imageamento Tridimensional , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptor de Pregnano X , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , Receptores de Esteroides/química , Receptores de Esteroides/metabolismo , Reprodutibilidade dos TestesRESUMO
1. Regulation of hepatic metabolism or transport may lead to increase in drug clearance and compromise efficacy or safety. In this study, cryopreserved human hepatocytes were used to assess the effect of 309 compounds on the activity and mRNA expression (using qPCR techniques) of CYP1A2, CYP2B6 and CYP3A4, as well as mRNA expression of six hepatic transport proteins: OATP1B1 (SCLO1B1), OCT1 (SLC22A1), MDR1 (ABCB1), MRP2 (ABCC2), MRP3 (ABCC3) and BCRP (ABCG2). 2. The results showed that 6% of compounds induced CYP1A2 activity (1.5-fold increase); 30% induced CYP2B6 while 23% induced CYP3A4. qPCR data identified 16, 33 or 32% inducers of CYP1A2, CYP2B6 or CYP3A4, respectively. MRP2 was induced by 27 compounds followed by MDR1 (16)>BCRP (9)>OCT1 (8)>OATP1B1 (5)>MRP3 (2). 3. CYP3A4 appeared to be down-regulated (≥2-fold decrease in mRNA expression) by 53 compounds, 10 for CYP2B6, 6 for OCT1, 4 for BCRP, 2 for CYP1A2 and OATP1B1 and 1 for MDR1 and MRP2. 4. Structure-activity relationship analysis showed that CYP2B6 and CYP3A4 inducers are bulky lipophilic molecules with a higher number of heavy atoms and a lower number of hydrogen bond donors. Finally, a strategy for testing CYP inducers in drug discovery is proposed.
Assuntos
Indutores do Citocromo P-450 CYP1A2/farmacologia , Indutores do Citocromo P-450 CYP2B6/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Hepatócitos/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/metabolismo , Técnicas de Cultura de Células , Indutores do Citocromo P-450 CYP1A2/química , Indutores do Citocromo P-450 CYP2B6/química , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/química , Descoberta de Drogas/métodos , Hepatócitos/enzimologia , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/química , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Transportadores de Ânions Orgânicos/química , Transportadores de Ânions Orgânicos/metabolismo , Transportador 1 de Cátions Orgânicos/química , Transportador 1 de Cátions Orgânicos/metabolismo , Relação Estrutura-AtividadeRESUMO
The pregnane X receptor (PXR) is one of the master regulators of xenobiotic transformation. Interactions between pharmacologic compounds and PXR frequently result in drug-to-drug interactions, drug-induced hepatotoxicity, and the development of drug-resistant phenotypes in cancer cells. Potential PXR-mediated effects on drug metabolism can be predicted using high-throughput methods to detect PXR transactivation. We used the reporter cell line nhrtox-hepg2 to screen an 1120-compound library of pharmacologic substances. Using a three-stage screening process combined with a quantitative structure-activity relationships (QSAR) analysis, we detected 16 novel, previously unreported PXR activators capable of upregulating CYP450 expression. For some of these compounds such as mycophenolic acid, leflunomide, and trifluridine, the observed interactions with PXR occurred at clinically significant concentrations and could provide potential mechanistic explanations for observed drug-to-drug interactions and drug-induced toxicity. A parallel QSAR analysis revealed significant correlation between the experimentally measured PXR-dependent bioactivity and the calculated molecular descriptors of the PXR activators.
Assuntos
Indutores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/biossíntese , Fígado/efeitos dos fármacos , Receptores de Esteroides/agonistas , Bibliotecas de Moléculas Pequenas , Simulação por Computador , Citocromo P-450 CYP3A/genética , Indutores do Citocromo P-450 CYP3A/química , Relação Dose-Resposta a Droga , Genes Reporter , Células Hep G2 , Humanos , Ligantes , Fígado/enzimologia , Modelos Moleculares , Estrutura Molecular , Receptor de Pregnano X , Relação Quantitativa Estrutura-Atividade , Receptores de Esteroides/metabolismo , TransfecçãoRESUMO
OBJECTIVE: To research and compare the influences of raw and processed Phellodendri Cortex on the cytochrome P450 four isoforms by Cocktail probe drugs, and to explore the processing principle of Phellodendri Cortex. METHODS: SD rats were randomly divided into raw group,processed with rice-wine group, processed with salt-water group and blank control group, which were given raw decoction, processed with rice-wine decoction, processed with salt-water decoction (3.24 g/kg) and normal saline respectively for one week, then given the mixture of four probe drugs on the 8th day, and soon after the blood samples were obtained through the orbits at a series of time-points. HPLC method was used to determine the concentrations of probe drugs in rat plasma, and pharmacokinetic parameters were estimated by DAS3.0. The effect of raw and processed Phellodendri Cortex on cytochrome P450 were judged indirectly by the pharmacokinetic parameters. RESULTS: Compared with the blank control group, the t½ significantly increased of theophylline in raw and processed with salt-water group. The CL/F significantly decreased and AUC(0-t) AUC(0-∞). significantly increased of theophylline in raw and processed with rice-wine groups. The t(½) AUC(0-∞) and AUC(0-∞) significantly decreased and CL/F significantly increased of dapsone in raw, processed with rice-wine and processed with salt-water group. The AUC(0-t) significantly increased of chlorzoxazone in raw and processed with salt-water group. The t(½), AUC(0-∞). and AUC(0-t) significantly decreased and CL/F significantly increased of chlorzoxazone in processed with rice-wine group. The AUC(0-t), significantly decreased of tolbutamide in raw, processed with rice-wine and processed with salt-water groups. CONCLUSION: The raw Phellodendri Cortex can inhibit CYP1A2, induce CYP3 A4 and also is need to make a further research work on CYP2C9 and CYP2E1. Meanwhile, it also can change the activities of cytochrome P450 after processed with rice-wine and salt-water. The Phellodendri Cortex processed with rice-wine can reduce the inhibitory effect of CYP1A2 and enhance induction of CYP3A4, it provides reference and basis to make an interpretation about Phellodendri Cortex processed with rice-wine.