https://orcid.org/0000-0003-4517-7021
Figures
Abstract
The objection of this study was to investigate the effects of vindoline(VDL) on the cytochrome P450 (CYP 450) isoforms (CYP1A2, 2B, 2C11, 2D1 and 3A) in rats. Firstly, the rats were randomly divided into VDL pretreatment group and blank group, each group had six rats. VDL pretreatment group was administrated VDL (20 mg·kg-1) by oral gavage for fifteen days consecutively, and the equivalent CMC-Na solution without VDL was given to the blank group by gavage. Secondly, a cocktail of caffeine, bupropion, diclofenac, dextromethorphan and midazolam was then administered on the sixteenth day. Finally, blood samples were collected at the specified time point, and the plasma concentration of the probe drug was determined by UHPLC-QTOF-MS/MS. The effects of VDL on the activity of these CYP enzymes in rats were evaluated by pharmacokinetic parameters. VDL pretreatment group compared with the blank group, accelerated the metabolism of diclofenac, and weakened the metabolism of caffeine. These results suggested that VDL could induce the activity of CYP2C11, and inhibits the activity of CYP1A2, but had no significant effects on CYP2B, CYP2D1 and CYP3A. The results in this study can provide beneficial information for the later clinical application of VDL.
Citation: Zhang Y, Niu H, Liu J, Xie W, Jin Y, Zhang Z (2023) Evaluation of the impact of vindoline, an active components of Catharanthus roseus, on rat hepatic cytochrome P450 enzymes by using a cocktail of probe drugs. PLoS ONE 18(8): e0289656. https://doi.org/10.1371/journal.pone.0289656
Editor: Chun-Hua Wang, Foshan University, CHINA
Received: February 21, 2023; Accepted: July 23, 2023; Published: August 3, 2023
Copyright: © 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: Yes This work was supported by Scientific Research Project of Hebei Administration Traditional Chinese Medicine [2021150]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
1. Introduction
Catharanthus roseus (L.) G. Don (C. roseus), an aboriginal perennial plant species of Madagascar, is often known as the Madagascar periwinkle [1, 2]. C. roseus is a tropical perennial subshrub known to produce about 130 alkaloids, such as vinblastine, vincristine, vinleurosine, vindoline, and catharanthine [3, 4]. In some countries, leaf and whole plant decoctions are used as home remedies for diabetes [5, 6]. Previous literature shows that the C. roseus leaf juice has significant antidiabetes activity, which may help prevent diabetes complications and play a good auxiliary role in the current antidiabetes drugs [5, 7]. Vindoline (VDL) is a semi-synthetic intermediate vinca alkaloid, which can be extracted from C roseus, it is reported to have anti diabetic properties in diabetes induced animal models [8, 9]. Recently, it was reported that VDL has the inhibitory effect on protein tyrosine phosphatase 1B (PTP-1B), so it can be used as an "insulin sensitizer" in the treatment of type 2 diabetes mellitus (T2DM) [10–12].
Diabetes is a lifelong metabolic diseases characterized by chronic hyperglycemia due to multiple etiologies [13]. According to the World Health Organization (WHO), diabetes has up to 100 complications, and which is currently one of the most known complications [14]. More than half of the deaths from diabetes were due to cardio cerebrovascular causes, and 10% were due to renal lesions. Clinical data shows that 30% - 40% of patients with diabetes will have at least one complication about 10 years after the onset of diabetes [15]. So diabetic patients usually take hypoglycemic drugs for a long time and even suffer from lifelong drug treatment, and it is often in combination with other drugs [16]. Taking multiple drugs at the same time can easily create drug-drug interactions (DDIs). As a potential hypoglycemic agent, VDL may be used in combination with other drugs. Therefore, it is necessary to clarify the effects of VDL on CYP enzymes activity [17].
The cytochrome P450 (CYP450) enzyme system has the greatest relationship with drug metabolism [18]. It mainly exists in human liver, and also has a small amount of expression in kidney, small intestine, lung and brain [19]. It participates in the biological transformation of many endogenous and exogenous substances (including most clinical drugs) of organisms [20]. DDIs should be considered in clinical use, mainly because there are many drugs that can enhance or weaken the activity of CYP (inducer), change the rate of drug metabolism, and affect the effect of drugs [21].
Recently a quadrupole time-of-flight mass (TripleTOF-MS) spectrometer has been routinely used as an effective and reliable analytical instrument [22]. The TripleTOF 5600+ system has a new ultra-high sensitivity designs, it can achieve high resolution and open a very narrow detection window without decreasing the sensitivity. At this time, it eliminates the interference of various impurities and has high selectivity. Therefore, the quantitative sensitivity can be comparable to the MRM sensitivity of API 4000 or API 5000; at the same time, the scanning speed as high as 100 spectra/s ensures that sufficient data points can be collected even for the peak width of UHPLC in a few seconds, so as to obtain excellent reproducibility and reliability.
Theoretically, human CYP1A2 is homolog to rat CYP1A2, human CYP2B is homolog to rat CYP2B, human CYP2C9 is homolog to rat CYP2C11, human CYP2D6 is homolog to rat CYP2D1 and human CYP3A4 is homolog to rat CYP3A [20, 23]. So rats were chosen as experimental animal in this research. To investigate the effects of VDL on rat hepatic CYP enzymes, this study adopted a probe cocktail approach using caffeine (CYP1A2), bupropion (CYP2B), dextromethorphan (CYP2C11), diclofenac acid (CYP2D1) and midazolam (CYP3A). Meanwhile, an ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS) method was used to detect these five probe drugs, which can provide a highly selective and sensitive assay with low limits of quantification.
2. Experimental
2.1 Chemicals and materials
The reference standards (purity>98%) of VDL (CAS:2182-14-1) were purchased from Shanghai Shifeng Biological Technology Co. Ltd. Caffeine, diclofenac sodium (purity≥99%) were purchased from China National Food and Drug Administration; Bupropion hydrochloride (purity≥98%) was purchased from Tokyo Institute of Physics and Chemistry; Dextromethorphan hydrobromide (purity≥98%) and phenacetin (purity≥99%) were purchased from Dalian Meilun Biotechnology Co., Ltd.; Midazolam (purity>98.0%) was purchased from J&KScientific Ltd. (Beijing, China). HPLC-grade acetonitrile and LC-MS grade formic acid were obtained from Fisher Chemicals (USA). Heparin Sodium Injection (for heparinizing centrifuge tubes) was purchased from Tianjin Biochem Pharmaceutical co., Ltd. (Tianjin, China). The other chemicals were all of analytical-reagent grade.
2.2 Instrumentations
Samples were analyzed by UHPLC-QTOF-MS/MS, which consisted of a ProminenceTM UHPLC System (Shimadzu, Japan) and a Triple TOFTM 5600+ system (AB SCIEX, USA) equipped with Duo-SprayTM ion sources in the electrospray ionization (ESI) technology.
2.3 Chromatographic conditions
The samples were separated by a Phenomenexkinetex C18 (3.0×50 mm, 2.6 μm), the column temperature was 40°C. The mobile phase consisted of 0.1% formic acid (A) and acetonitrile (B) at a flow rate of 400 μL·min-1, the gradient elution program was established as 0–0.5 min, 20% B; 0.5–4 min, 20–95% B; 4–5 min, 95% B; 5–5.1 min, 95–20% B. The injection volume was 2 μL.
2.4 Mass spectrometric conditions
The mass detection was accomplished in multiple reaction monitoring (MRMHR) mode. Analyst® TF 1.7 software (AB SCIEX, USA) and MultiQuant 3.0.1 (AB SCIEX, USA) were used for instrument control, data acquisition as well as data processing. The ESI source was set to positive ion mode with ionization conditions as follows: ion spray voltage floating, (+) 5.5 kV; ion source heater, 550°C; curtain gas, 25 psi; ion source gas 1, 55 psi; and ion source gas 2, 55 psi. The detected ions and collision energy (CE) of the five cocktail probe drugs are shown in Table 1. The collision energy expansion (CES) is 0 eV. A narrow extraction window (±0.02 Da) was used in MultiQuant 3.0.1 to leverage the high resolution data.
2.5 Standard and sample preparation
2.5.1 Preparation of calibration curve samples and quality control (QC) samples.
Five probe drug stock solutions with a concentration of 1mg/mL were prepared in methanol. A series of working solutions were obtained by diluting the stock solution with methanol. Additionally, the phenacetin (IS) working solution was obtained by diluting the stock standard solution with methanol to yield the final concentration of 0.2 μg/mL. All the solutions were stored at 4°C until analysis.
Add the working solution into 100 μL blank plasma to prepare the calibration standards and quality control (QC) samples. The final plasma concentrations of calibration samples were adjusted to 3.007, 15.015, 30.07, 60.24, 300.7, 602.4, 1501.5, 3007 ng/mL for caffeine; 0.3075, 1.537, 3.075, 6.150, 30.75, 61.50, 153.7, 307.5 ng/mL for bupropion; 0.2032, 1.016, 2.032, 4.064, 20.32, 40.64, 101.6, 203.2 ng/mL for dextromethorphan; 2.907, 14.535, 29.07, 58.14, 290.7, 581.4, 1453.5, 2907 ng/mL for diclofenac; 0.5000, 2.500, 5.000, 10.00, 50.00, 100.0, 250.0, 500.0 ng/mL for midazolam. Quality control (QC) samples, including low, medium, high concentration and lower limit of quantification (LLOQ) levels, with final concentrations of 7.962, 300.7, 2255, 3.007 ng/mL for caffeine; 0.7688, 30.75, 230.6, 0.3075 ng/mL for bupropion; 7.267, 290.7, 2180, 2.907 ng/mL for diclofenac; 0.5080, 20.32, 152.4, 0.2032 ng/mL for dextromethorphan; 1.250, 50.00, 375.0, 0.500 ng/mL for midazolam.
2.5.2 Sample preparation.
10 μL of methanol and 10 μL of IS working solution were added into 100 μL of rat plasma sample. Then adding 300 acetonitrile to precipitate protein, the mixture was vortexed for 5min, and centrifuged at 15000 rpm for 10min, the supernatant was transferred to another tube, evaporated to dryness under a stream of nitrogen. The residue was reconstituted with 150 μL of 80% acetonitrile and centrifuged at 15000 rpm for 10 min. Before injection, 2 μL of supernatant was used for UHPLC-QTOF-MS/MS analysis.
2.6 Application of the analytical method in CYP450 activity study
Male Sprague–Dawley rats (Certificate No.SCXK 2013-1-003; weighting 250±20g; 7–8 weeks of age) were supplied by the Experimental Animal Center of Hebei Laboratory Animal Center (Shijiazhuang, China). Before the experiment, rats were fed in a breeding room with a temperature of 22–25° C, a relative humidity of 55–60% and a 12h light/dark cycle for a week. During this period, rats ate and drank normally, and fasted overnight before administration. All experiments on rats were conducted in accordance with the guidelines of the Committee on the Care and Use of Laboratory Animals in our laboratory.
The rats were randomly divided into two groups: the VDL pretreatment group and the blank group, six rats in each group. The blank group took 5% CMC-Na solution orally for 15 days; the VDL treated groups were administered quantitatively VDL (20mg·kg-1) [7] for 15 consecutive days; On the sixteenth day, the VDL treated group and the blank group were administrated mixed cocktail probe drugs, which included caffeine (5mg·kg-1; for CYP1A2 activity), bupropion (5 mg·kg-1; for CYP2B activity); diclofenac (5mg·kg-1; for CYP2C11 activity), dextromethorphan (5mg·kg-1; for CYP2D1 activity) and midazolam(5 mg·kg-1; for CYP3A activity). Blood samples were collected from the epicanthic veins at 0 (pre-dose), 0.08 (5 min), 0.25 (15 min), 0.5 (30 min), 0.75 (45 min), 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h, and transfered it to the heparinized centrifuge tube. Then the tubes with blood samples centrifuged at 4500 g for 5 min, and transfer 0.1mL of plasma layer into a clean centrifuge tube and store it at -80°C. At the end of this study, the animals were anesthetized under 3% isoflurane and euthanized by exsanguination via cardiac puncture [24].
2.7 Statistical analysis
The pharmacokinetic parameters of the five probe drugs were derived with a non-linearre gression iterative program, and calculated with the DAS 3.0 pharmacokinetic program (Chinese Pharmacological Society, Beijing, China). The statistical analysis used SPSS 21.0 (IBM SPSS, USA), and compared the pharmacokinetic characteristics of five probe drugs with One-way analysis of variance (ANOVA). When P<0.05, the difference was considered statistically significant.
3. Results
An efficient and reliable UHPLC-MS method for simultaneous determination of caffeine, bupropion, diclofenac, dextromethorphan, and midazolam is established, thus can be applied to activity evaluation of CYP1A2, 2B, 2C11, 2D1 and 3A with a cocktail approach.
3.1 Method validation
The chromatograms of the blank plasma samples, blank plasma samples spiked with analytes at LLOQ and plasma samples from rats 1h after oral administration of cocktail solution are shown in Fig 1. The calibration curves were obtained by using a weighting factor of 1/x2. The calibration curves, linear ranges, correlation coefficients and LLOQs of the five cocktail probe drugs are shown in Table 2. The real values of each calibration concentration were between 89% and 112% of the theoretical values. None of the RE and RSD values of the intra-day and inter-day accuracy and precision exceeded 15%.
Note: (A) blank plasma; (B) blank plasma spiked with cocktail probe drugs at LLOQ and IS; (C) sample plasma 1 h after administration of cocktail solution.
3.2 Effects of VDL on CYP450 activities in rats
The concentration-time curves and pharmacokinetic parameters are shown in Figs 2–6 and Tables 3–7, respectively.
By comparing the pharmacokinetic parameters of blank group and VDL pretreatment group, VDL weakened the metabolism of caffeine, by increasing t1/2 (78.92%, p<0.05), Cmax (36.78%, p<0.05), AUC0-t (66.52%, p<0.05), AUC0-∞ (65.74%, p<0.05), and decreasing caffeine clearance (CL) (46.88%, p<0.05). In addition, VDL pretreatment accelerated the metabolism of diclofenac by decreasing t1/2 (37.67%, p<0.05), Cmax (47.95%, p<0.05), AUC0-t (48.70%, p<0.05), AUC0-∞ (51.79%, p<0.05) and increasing diclofenac clearance (CL) (51.79%, p<0.05). But no significant differences were observed in the major pharmacokinetics parameters of bupropion, dextromethorphan and midazolam between the VDL group and the blank group, which meant that there were no effects of VDL on CYP2B, CYP2D1 and CYP3A.
4. Discussion
4.1 Cocktail probe drugs method
The cocktail probe drugs method is a screening tool to predict the enzyme activity. In 1990, Breimer, DD et al. first used multiple probe substrates simultaneously to evaluate the activity of multiple CYP450 subtypes of enzymes, which called “Cocktail probe drug approach”. This approach is capable of measurement the activity of multiple CYP enzymes after the administration of multiple CYP-specific substrates in a single experiment.
The Vmax and Km values of cocktail probe drug approach and single probe approach are consistent, thus cocktail probe drug approach can replace single probe approach for the evaluation of CYP450 activity [25]. So far, the cocktail method can allow fast routine measurement of the multiple CYP enzyme activities in a single experiment, and this method also can minimize the confounding influence of inter-individual and intra-individual variability [21, 26, 27]. Therefore, the cocktail method is a powerful tool for comprehensively evaluating drug interactions involving multiple CYP enzymes simultaneously.
According to the “Drug Interaction Research” guidelines released by the FDA in the United States [28], the selection of in vivo study probe drugs depends on the CYP450 enzyme. Generally, probe drugs that specifically bind to isoenzymes should be selected. Therefore, according to the recommended guidelines, we have chosen the following probe drugs: (1) Midazolam (CYP3A); (2) Caffeine (CYP1A2); (3) Bupropion (CYP2B); (4) Diclofenac (CYP2C9); (5) Dextromethorphan (CYP2D6). In the experiment, the selection of probe drug dosage is also very important. The dose range of the probe drug was determined through literature [29–31], then preliminary experiments were conducted to determine the actual dosage, ensuring that low doses of composite probes were administered to experimental animals within the allowable range of detection capabilities, which can reduce the possibility of potential drug-drug interactions between probe drugs [21]. Finally, we determine the dose of the probe drugs, which is caffeine 5 mg·kg -1, bupropion 5 mg·kg -1, diclofenac 5mg·kg -1, dextromethorphan 5mg·kg -1, midazolam 5 mg·kg-1.
4.2 Induction and inhibition of CYP450 isoform activity by VDL
In the treatment of diabetes, patients usually need to take multiple drugs, and the combination of multiple drugs is very likely to cause DDIs [32]. If several drugs are metabolized through the same enzyme, the drug efficacy will increase or decrease, which will lead to treatment failure [33]. As a potential anti diabetes drug, it is necessary to study the effect of VDL on enzyme activity. In this study, we found that VDL tended to be the inducer of CYP2C11 (CYP2C9 in human). Stephen S. et al. reported that the nuclear receptor CAR (Constitutive androgen receptor) as an effective regulator of CYP2C9 transcription at both the mRNA level and in promoter assays [34]. So we think that VDL might upregulate the transcription level of CYP2C9 through the CAR receptor. In addition, we found that VDL had an inhibitive effect on CYP1A2. It is reported that nitrogen-containing heterocyclic compounds can bind tightly to the prosthetic haem iron of CYP proteins; this binding often exhibits reversible inhibition on CYP enzymes [35]. VDL is a single indole alkaloid, which have nitrogen-containing pyrrole rings. So we think that the inhibitory effect of VDL on CYP1A2 may be related to the nitrogen-containing heterocycles in VDL.
The induction of CYP leads to the increase of the synthesis or activity of CYP, thus accelerating the metabolism of drugs eliminated by this procedure, leading to the reduction of plasma drug concentration and treatment delay [36]. In this study, treatment of rats with VDL decreased the t1/2, Cmax, AUC0-t, AUC0-∞ and increased clearance (CL) of diclofenac compared with those in the blank control. It is suggested that VDL could induce CYP2C11, which is homolog to human CYP2C9. CYP2C9 is one of the most important metabolic enzymes in the CYP enzyme family. About 15% of clinical drugs are metabolized by CYP2C9, including celecoxib, phenytoin sodium, diazepam, tolbutamide, diclofenac acid, losartan and S-warfarin [37, 38]. In clinic, when applied in combination, VDL may interact with all drugs metabolized by CYP2C9, especially for drugs with a narrow therapeutic window, such as phenytoin sodium. Therefore, VDL should be avoided in combination with these drugs.
According to the experimental results, the activity of CYP1A2 might be inhibited by VDL. Enzyme inhibition refers to those drugs can inhibit the activity of enzymes during the combined use of drugs, resulting in slower metabolism of the combined drugs, making the concentration of drugs in the body higher than the normal concentration when used alone, and enhancing the effect [35]. For drugs with narrow treatment window, serious adverse reactions may occur [39]. CYP1A2 accounts for only 13% in the CYP enzyme family, but many important marketed drugs are metabolized by CYP1A2 [40]. In the future clinical application of VDL, it is likely to be combined with many drugs, including antihypertensive drugs, hypoglycemic drugs, and lipid-lowering drugs and so on [41], if the main metabolic enzyme of these drugs is CYP1A2, because VDL has an inhibitory effect on CYP1A2, the plasma concentration of these drugs will increase compared with the concentration when they are used alone, which can cause adverse effects, and may endanger life in serious cases [42, 43].
4.3 Analysis of in vitro and in vivo experimental results
In the previous in vitro experiments, it was found that VDL could inhibit CYP2D1 activity, and had weak inhibitory effect on CYP2C11 and CYP3A (S1 Fig), which was inconsistent with the results of in vivo experiments [44]. The reasons for this phenomenon may be as follows: (1) Influence of in vivo and in vitro action time and dosage: in vitro experiments, VDL and probe drugs were directly incubated with CYP450 enzymes in rat liver microsome, while in vivo experiments, rats were pretreated with VDL for 15 days, and then the probe substrate was administered on the 16 days. The expression environment of the enzyme, and the dosage in rat are differences, it may cause VDL to induce or inhibit the CYP450 enzyme in different ways. (2) Compared with in vivo experiment, the environment of the enzymatic reaction was artificially simulated in vitro, and the interference of other complex factors in the body was excluded. But in vivo experiments reflect the metabolism of drugs in the physiological state of the whole living organism. This difference of in vitro and in vivo environment may cause changes in the activity and quantity of CYP450 enzymes, which may lead to inconsistencies in the results of in vitro and in vivo experiments [45]. This study suggested that examining the effects of drugs on CYP450 enzyme activity, in vitro and in vivo experiments are equally important. Preliminary exploration of in vitro experiments can provide ideas for further in vivo experiments, but whether the in vitro experimental data can be used to directly predict the interaction results in vivo remains to be further verified.
5. Conclusion
In this study, the in vivo results was showed that VDL inhibited the activity of CYP1A2, and induced the activity of CYP2C9, but had no effects on the activities of CYP2B, CYP2D6 and CYP3A4. Based on the above findings, we need follow with interest potential DDIs regulated by CYP1A2 and 2C9, when VDL combined with other drugs (particularly for drugs with narrow therapeutic window). However, the relevant research and clinical significance of human still need further study.
Supporting information
S1 Fig. The inhibition curves of VDL on five CYP450 isoforms (
± s, n = 6).
https://doi.org/10.1371/journal.pone.0289656.s001
(TIF)
References
- 1. Soumya V, Sowjanya A, Kiranmayi P. Evaluating the status of phytochemicals within Catharanthus roseus due to higher metal stress. Int J Phytoremediation. 2021; 23(13): 1391–1401. pmid:33735592
- 2. Gupta M.M., Singh D.V., Tripathi A.K., Pandey R., Verma R.K., Singh S., et al. Simultaneous determination of vincristine, vinblastine, catharanthine, and vindoline in leaves of Catharanthus roseus by high-performance liquid chromatography. J Chromatogr Sci. 2005; 43(9):450–3. pmid:16212789
- 3. Zhang L., Gai Q.H., Zu Y.G., Yang L., Ma Y.L., Liu Y. Simultaneous quantitative determination of five alkaloids in Catharanthus roseus by HPLC-ESI-MS/MS. Chin J Nat Med. 2014; 12(10): 786–793. pmid:25443373
- 4. Chaudhary S., Pandey R., Tripathi B.N., Goel R., Kumar S. Detection and mapping of quantitative trait loci for the contents of the terpenoid indole alkaloids, vindoline and catharanthine, in the leaves of Catharanthus roseus using bulk segregant analysis. J Hortic Sci Biotech. 2015; 87 (2);
- 5. Nammi Srinivas, Murthy K Boini, Srinivas D Lodagala, Ravindra Babu S Behara. The juice of fresh leaves of Catharanthus roseus Linn. reduces blood glucose in normal and alloxan diabetic rabbits. BMC Complement Altern Med. 2003; 3(4): 1–4. pmid:12950994
- 6. Rasineni K, Bellamkonda R, Singareddy SR, Desireddy S. Antihyperglycemic activity of Catharanthus roseus leaf powder in streptozotocin-induced diabetic rats. Pharmacognosy Res. 2010; 2(3):195–201. pmid:21808566
- 7. Yao X.G., Chen F.L., Li P., Quan L.L., Chen J., Yu L., et al. Natural product vindoline stimulates insulin secretion and efficiently ameliorates glucose homeostasis in diabetic murine models. J. Ethnopharmacol. 2013; 150(1): 285–297. pmid:24012527
- 8. Magnotta Mary, Murata Jun, Chen Jianxin, Vincenzo De Luca. Identification of a low vindoline accumulating cultivar of Catharanthus roseus (L.) G. Don by alkaloid and enzymatic profiling. Phytochemistry. 2006; 67(16):1758–64. pmid:16806326
- 9. Oguntibeju O. O., Aboua Y., Kachepe P. Possible therapeutic effects of vindoline on testicular and epididymal function in diabetes-induced oxidative stress male wistar rats. Heliyon. 6 (2020) e03817. 2020; 6(4):e03817. pmid:32373734
- 10. Goboza Mediline, Aboua Yapo G., Chegou Novel, Oguntibeju Oluwafemi O. Vindoline effectively ameliorated diabetes-induced hepatotoxicity by docking oxidative stress, inflammation and hypertriglyceridemia in type 2 diabetes-induced male wistar rats. Biomed Pharmacother. 2019; 112:108638. pmid:30784928
- 11. Goboza Mediline, Meyer Mervin, Aboua Yapo G., Oguntibeju Oluwafemi O. In Vitro antidiabetic and antioxidant effects of different extracts of Catharanthus roseus and its indole alkaloid, vindoline. Molecules. 2020; 25(23):5546. pmid:33256043
- 12. Oluwafemi Omoniyi Oguntibeju Yapo Aboua, Goboza Mediline. Vindoline-a natural product from Catharanthus roseus reduces hyperlipidemia and renal pathophysiology in experimental type 2 diabetes. Biomedicines. 2019;7(3):59. pmid:31412679
- 13. Nathan David M, Buse John B, Davidson Mayer B, Ferrannini Ele, Holman Rury R, Sherwin Robert, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the american diabetes association and the european association for the study of diabetes. Diabetes Care. 2009; 32(1):193–203. pmid:18945920
- 14. Gravel Sophie, Chiasson Jean-Louis, Turgeon Jacques, Grangeon Alexia, Michaud Veronique. Modulation of CYP450 activities in patients with type 2 diabetes. Clin Pharmacol Ther. 2019; 106(6):1280–1289. pmid:31099895
- 15. Leung A, Natarajan R. Long noncoding RNAs in diabetes and diabetic complications. Antioxid Redox Signal. 2018; 29(11):1064–1073. pmid:28934861
- 16. Jiang Xue, Meng Weiqi, Li Lanzhou, Meng Zhaoli, Wang Di. Adjuvant therapy with mushroom polysaccharides for diabetic complications. Front Pharmacol. 2020; 11:168. pmid:32180724
- 17. Labib Al-Musawe Carla Torre, Jose Pedro Guerreiro Antonio Teixeira Rodrigues, Joao Filipe Raposo Helder Mota-Filipe, et al. Polypharmacy, potentially serious clinically relevant drug-drug interactions, and inappropriate medicines in elderly people with type 2 diabetes and their impact on quality of life. Pharmacol Res Perspect. 2020; 8(4):e00621. pmid:32618136
- 18. Zanger U.M, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013; 138(1):103–41. pmid:23333322
- 19. Cheng PY, Morgan ET. Hepatic cytochrome P450 regulation in disease states. Curr Drug Metab. 2001; 2(2):165–83. pmid:11469724
- 20. Gravel Sophie, Chiasson Jean Louis, Dallaire Suzanne, Turgeon Jacques, Michaud Veronique. Evaluating the impact of type 2 diabetes mellitus on CYP450 metabolic activities: protocol for a case-control pharmacokinetic study. BMJ Open. 2018; 8(2):e020922. pmid:29439084
- 21. Sun Y., Liu Y., Zhang X., Wan C., Zhang L. Effects of m -nisoldipine on the activity and mRNA expression of four CYP isozymes in rats. Xenobiotica. 2018; 48(7):676–683. pmid:28756727
- 22. Yin Jintuo, Ma Yinling, Liang Caijuan, Gao Jin, Wang Hairong, Zhang Lantong. A systematic study of the metabolites of dietary acacet in in vivo and in vitro based on UHPLC-Q-TOF-MS/MS analysis. J Agric Food Chem. 2019; 67(19):5530–5543. pmid:31025561
- 23. Chen Jing ya, tao Huang Xiang, jun Wang Jun, Chen Yong. In vivo effect of borneol on rat hepatic CYP2B expression and activity. Chem Biol Interact. 2017; 261:96–102. pmid:27889497
- 24. Marilia Hermes Cavalcanti João Paulo Santos Roseira, Eliana Dos Santos Leandro, Sandra Fernandes Arruda. Effect of a freeze-dried coffee solution in a high-fat diet-induced obesity model in rats: impact on inflammatory response, lipid profile, and gut microbiota. PLoS One. 2022; 17(1):e0262270. pmid:35081143
- 25. D D Breimer J H Schellens. A cocktail strategy to assess in vivo oxidative drug metabolism in humans. Trends Pharmacol Sci. 1990; 11(6):223–5. pmid:2200179
- 26. Frye RF, Matzke GR, Adedoyin A, Porter JA, Branch RA. Validation of the five-drug “Pittsburgh cocktail” approach for assessment of selective regulation of drug metabolizing enzymes. Clin Pharmacol Ther. 1997; 62: 365–376. pmid:9357387
- 27. Ryu J Y, Song I S, Sunwoo Y E, Shon J H, Liu K H, Cha I J, et al. Development of the ‘Inje cocktail’ for high-throughput evaluation of five human cytochrome P450 isoforms in vivo. Clin Pharmacol Ther. 2007; 82(5):531–40. pmid:17392720
- 28. Food U, Food D A. Guidance for industry-drug interaction studies: study design, data analysis, implications for dosing, and labeling recommendations. 2012.
- 29. Shi Yong, Meng Deru, Wang Shuanghu, Geng Peiwu, Xu Tao, Zhou Quan, et al. Effects of avitinib on CYP450 enzyme activity in vitro and in vivo in rats. Drug Des Devel Ther. 2021; 15:3661–3673. eCollection 2021. pmid:34456561
- 30. Zheng Lin, Lu Yuan, Cao Xu, Huang Yong, Liu Yue, Tang Li, et al. Evaluation of the impact of Polygonum capitatum, a traditional chinese herbal medicine, on rat hepatic cytochrome P450 enzymes by using a cocktail of probe drugs. J Ethnopharmacol. 2014; 158 Pt A:276–82. pmid:25446640
- 31. Qiang Tingting, Li Yiping, Wang Keyan, Lin Wenyong, Niu Zhenchao, Wang Dan, et al. Evaluation of potential herb-drug interactions based on the effect of Suxiao Jiuxin Pill on CYP450 enzymes and transporters. J Ethnopharmacol. 2021; 280:114408. pmid:34252529
- 32. McCracken R, McCormack J, McGregor MJ, Wong ST, Garrison S. Associations between polypharmacy and treatment intensity for hypertension and diabetes: a cross-sectional study of nursing home patients in British Columbia, Canada. BMJ Open. 2017; 7(8):e017430. pmid:28801438
- 33. Carter B.L., Lund B.C., Hayase N, Chrischilles E. The extent of potential antihypertensive drug interactions in a Medicaid population. Am J Hypertens. 2002; 15(11):953–7. pmid:12441214
- 34. Ferguson Stephen S, LeCluyse Edward L, Negishi Masahiko, Goldstein Joyce A. Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site. Mol Pharmacol. 2002; 62(3):737–46. pmid:12181452
- 35. Yan Zheng, Caldwell Gary W. Metabolism profiling, and cytochrome P450 inhibition & induction in drug discovery. Curr Top Med Chem. 2001; 1(5):403–25. pmid:11899105
- 36. Gonzalez Frank J. The 2006 Bernard B. Brodie award lecture. Cyp2e1. Drug Metab Dispos. 2007; 35(1):1–8. pmid:17020953
- 37. Wang Kai, Gao Qing, Zhang Tingting, Rao Jinqiu, Ding Liqin, Qiu Feng. Inhibition of CYP2C9 by natural products: insight into the potential risk of herb-drug interactions. Drug Metab Rev. 2020; 52(2):235–257. pmid:32406758
- 38. Semiz Sabina, Dujic Tanja, Ostanek Barbara, Prnjavorac Besim, Bego Tamer, Malenica Maja, et al. Analysis of CYP2C9*2, CYP2C19*2, and CYP2D6*4 polymorphisms in patients with type 2 diabetes mellitus. Bosn J Basic Med Sci. 2010; 10(4):287–91. pmid:21108610
- 39. Yu Yue, Liu Yan, Li Qian, Sun Jiahui, Lin Haiou, Liu Gaofeng. Effects of Guanxinning injection on rat cytochrome P450 isoforms activities in vivo and in vitro. Xenobiotica. 2015; 45(6):481–7. pmid:25495039
- 40. Shimada T, Yamazaki H, Mimura M, Y Inui, F P Guengerich. Inter-individual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994 Jul; 270(1):414–23. pmid:8035341.
- 41. Papatheodorou K., Papanas N., Banach M., Papazoglou D., Edmonds M. Complications of diabetes 2016. J. Diabetes Res. 2016, 6989453. pmid:27822482
- 42. Yu Jingjing, Wang Yan, Isabelle Ragueneau-Majlessi. Strong pharmacokinetic drug-drug Interactions with drugs approved by the U.S. food and drug administration in 2021: mechanisms and clinical implications. Clin Ther. 2022; 44(11):1536–1544. pmid:36210218
- 43. Yu Jingjing, Petrie Ichiko D, Levy René H, Isabelle Ragueneau-Majlessi. Mechanisms and clinical significance of pharmacokinetic-based drug-drug interactions with drugs approved by the U.S. food and drug administration in 2017. Drug Metab Dispos. 2019; 47:135–144. pmid:30442649
- 44. Zhang Yuqian, Xie Weiwei, Liu Jian, Zhang Zhiqing, Jin Yiran. Effects of vindoline on rat cytochrome P450 isoform activities in vitro. Biomed Chromatogr. 2022; 36(8):e5409. pmid:35562325
- 45. Wei Chen, Ruixi He, Hui Peng, Yanyan Zhu, Daiyin Peng, Weidong Chen. Effects of gambogic acid on the enzymatic activity of cytochrome P450 isoforms in rat liver microsomes. J Anhui Univ Chin Med. 2016, 35(1):6.