Cytochrome P450 inhibition to decrease dosage and costs of venetoclax and ibrutinib: A proof-of-concept case study.

The inhibition of cytochrome P450 (CYP) enzymes is the most frequent cause of drug-drug interactions. Many safe, inexpensive and widely available therapeutic drugs can inhibit CYP enzymes (e.g., azoles). Also, the specific potency of inhibition and the targeted CYP enzyme have been well described (e.g., itraconazole strongly inhibits CYP enzyme 3A4 and, in turn, CYP3A4 metabolizes venetoclax and ibrutinib). CYP enzyme inhibitors increase the plasma concentration of other drugs via shared metabolic pathways. We herein present the effects of inhibiting CYP enzymes with itraconazole-venetoclax for the treatment of refractory acute myeloid leukaemia, as well as itraconazole-ibrutinib to treat steroid-refractory acute graft vs. host disease in the same patient. Both of the patient's conditions responded completely. This appears to be a feasible strategy that decreases treatment costs by 75%. Previous Food and Drug Administration recommendations and clinical data support these subsequent dose reductions. Eleven months after the transplant, the patient remains in complete response and with no minimal residual disease. Another patient had been effectively treated before with CYP enzyme inhibition prior to venetoclax-itraconazole administration for orbital myeloid sarcoma. Thus, this case study furthers information on the CYP enzyme inhibition strategy when associated with another costly drug, ibrutinib. The CYP enzyme inhibition strategy could be applied to many more anticancer drugs (e.g., ruxolitinib and ponatinib) and facilitate the availability of expensive oncological treatments in low- and middle-income countries. Also, this strategy could be further generalized by using different CYP enzyme inhibitors with varied pharmacokinetic and pharmacodynamic properties (i.e., grapefruit, azoles and clarithromycin).

Inhibition of Cytochrome P450 Enzyme and Drug-Drug Interaction Potential of Acid Reducing Agents Used in Management of CDK Inhibitors for Breast Cancer Chemotherapy.

BACKGROUND AND OBJECTIVE: Concurrent usage of proton pump inhibitors and their effect on survival and medication termination has been found in individuals receiving protein kinase inhibitor chemotherapy. To investigate the drug-drug interaction mechanism between CDK inhibitors and proton pump inhibitors, the in-silico docking approach was designed by applying computer simulation modules to predict the binding and inhibitory potential. METHODS: The interaction potential of proton pump inhibitors and CDK inhibitors was predicted utilising molecular docking techniques that employed Schrödinger algorithms to capture the dynamics of the CYP450 enzyme-inhibitor interaction between proton pump inhibitors and CDK inhibitors. Additionally, the human liver microsomes assay was used to determine the in vitro half-maximal inhibitory concentration (IC50) of proton pump inhibitors and the inactivation of CDK inhibitors via CYP3A4. RESULTS: Proton pump inhibitors alter the conformation of the CYP3A4 and CYP2C19 enzymes and interact with the heme prosthetic group, as determined by docking studies. It may result in the suppression of CDK inhibitors' metabolism via competitive inhibition at the binding site of an enzyme. Omeprazole and rabeprazole both significantly block midazolam's 1'-hydroxylation by CYP3A4 in vitro, with IC50 values of 9.86µM and 9.71µM, respectively. When omeprazole and rabeprazole are co-incubated in human liver microsomes at a 30µM concentration equivalent to the Cmax of omeprazole and rabeprazole, rabeprazole significantly prolongs the metabolic clearance of palbociclib, whereas omeprazole affects the ribociclib CYP3A4-mediated metabolism. CONCLUSION: Using dynamic models, we determined that proton pump inhibitors such as rabeprazole and omeprazole indeed have the potential to cause clinically significant drug-drug interactions with CDK inhibitors in the treatment of estrogen receptor (ER) positive and HER2-positive breast cancer. As a result, it is suggested to use caution when prescribing proton pump inhibitors to these individuals.

Harnessing the mitochondrial integrity for neuroprotection: Therapeutic role of piperine against experimental ischemic stroke.

Ischemic stroke (IS) is a rapidly increasing global burden and is associated with severe neurological decline and mortality. There is urgent requirement of the efforts, aimed to identify therapeutic strategies that are effective in clinic to promote significant recovery from IS. Studies have shown that mitochondria mediated neuroprotection can be a competent target against ischemic damage. Therefore, we examined whether mitochondrial impairment is regulated by Piperine (PIP), an alkaloid of Piper Longum, which has neuroprotective activity against ischemic brain injury. In this study, transient middle cerebral artery occlusion (tMCAO) surgery was performed on male Wistar rats for 90 min followed by 22.5 h of reperfusion for mimicking the IS condition. This study consisted of three groups: sham, tMCAO and tMCAO + PIP (10 mg/kg b.wt., p.o/day for 15 days), and studied for behavioral tests, infarct volume, brain pathological changes, mitochondrial dysfunction, inflammation alongwith cell survival status. PIP pre-treatment showed reduction in neurological alterations and infarct volume. In addition, PIP pre-treatment suppressed the mitochondrial dysfunction and might have anti-apoptotic potential by preventing Cytochrome c (Cyt c) release from mitochondria to cytoplasm and caspase 3 activation. It also regulates pro-apoptotic, Bax and anti-apoptotic, Bcl-2 proteins accompanied by glial fibrillary acidic protein (GFAP) positive cells in cortex region. Quantitative Reverse transcription-polymerase chain reaction (qRT-PCR) results also showed that PIP reduced the expression of pro-inflammatory protein, interleukin-1 ß (IL-1ß) and enhanced cell survival by restoring the activity of brain derived neurotrophic factor (BDNF) and its transcription protein, cAMP response element binding protein (CREB). Taken together, PIP reduced the mitochondrial dysfunction, neurological impairment, and enhanced neuronal survival. In conclusion, our findings reinforce PIP as an effective neuroprotective agent and provide important evidence about its role as a potential target to serve as a promising therapy for treatment of IS.

Cannabinoid Interactions with Cytochrome P450 Drug Metabolism: a Full-Spectrum Characterization.

Medicinal cannabis use has increased exponentially with widespread legalization around the world. Cannabis-based products are being used for numerous health conditions, often in conjunction with prescribed medications. The risk of clinically significant drug-drug interactions (DDIs) increases in this setting of polypharmacy, prompting concern among health care providers. Serious adverse events can result from DDIs, specifically those affecting CYP-mediated drug metabolism. Both cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), major constituents of cannabis, potently inhibit CYPs. Cannabis-based products contain an array of cannabinoids, many of which have limited data available regarding potential DDIs. This study assessed the inhibitory potential of 12 cannabinoids against CYP-mediated drug metabolism to predict the likelihood of clinically significant DDIs between cannabis-based therapies and conventional medications. Supersomes™ were used to screen the inhibitory potential of cannabinoids in vitro. Twelve cannabinoids were evaluated at the predominant drug-metabolizing isoforms: CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2B6, and CYP2C19. The cannabinoids exhibited varied effects and potencies across the CYP isoforms. CYP2C9-mediated metabolism was inhibited by nearly all the cannabinoids with estimated Ki values of 0.2-3.2 µM. Most of the cannabinoids inhibited CYP2C19, whereas CYP2D6, CYP3A4, and CYP2B6 were either not affected or only partially inhibited by the cannabinoids. Effects of the cannabinoids on CYP2D6, CYP1A2, CYP2B6, and CYP3A4 metabolism were limited so in vivo DDIs mediated by these isoforms would not be predicted. CYP2C9-mediated metabolism was inhibited by cannabinoids at clinically relevant concentrations. In vivo DDI studies may be justified for CYP2C9 substrates with a narrow therapeutic index.

Interpretation of Cytochrome P-450 Inhibition and Induction Effects From Clinical Data: Current Standards and Recommendations for Implementation.

Agents that modify cytochrome P-450 (CYP) enzyme activity are characterized as strong, moderate, or weak inhibitors or inducers based on the magnitude of their impact on substrate exposure in clinical studies. Criteria for these classifications are simple and semiquantitative. However, assignment of a given agent to a CYP inhibitor or inducer category is often complicated by limitations of the published data, inconsistent study findings, and other factors. CYP inhibitor and inducer categories are commonly used as a basis for differentiating drug interaction management recommendations. For example, product labeling for a CYP substrate may recommend avoidance in combination with strong inhibitors and dose reduction in combination with moderate inhibitors. When such recommendations exist, ambiguity or variability in placement of inhibitors or inducers into categories can introduce potentially harmful variations in clinical drug interaction management. Failure to adequately reflect the drug interaction potential of an agent by under-categorizing it (e.g., calling it weak when data point to moderate effects), for example, may lead clinicians to respond inadequately to real risks, or to ignore potential interactions altogether. Over-categorization may lead to actions such as over-adjustment of substrate doses or unnecessary avoidance of optimal treatments. This review describes the current criteria for assignment of CYP inhibitor and inducer categories, summarizes common circumstances leading to ambiguous or variable CYP inhibitor and inducer categorizations, and proposes an approach to data interpretation and application of current criteria under uncertainty. When applied to > 1,000 CYP reviews, the approach described has identified a clear categorization in almost all cases.

Aldosterone synthase inhibitors for cardiovascular diseases: A comprehensive review of preclinical, clinical and in silico data.

Aldosterone, the main mineralocorticoid hormone, plays a fundamental role in maintaining blood pressure (BP)and volume under hypovolemic conditions. However, in numerous diseases, where it is produced in excess, it plays a detrimental role and contributes to cardiovascular events and ultimately to death in a multitude of patients. The seminal observation that the fungicide-derivative fadrozole blunted steroidogenesis has led to develop several agents to inhibit aldosterone synthase (AS, CYP11B2), the mitochondrial NADH-dependent enzyme that is necessary for aldosterone biosynthesis. Aldosterone synthase inhibitors (ASI) have, thereafter, been conceived and investigated in phase I and phase II studies. We herein reviewed the ASIs available so far considering their chemical structure, the related aldosterone synthase binding and pharmacodynamic properties. We also examined the promising results obtained with ASIs that have already been tested in phase II human studies.

Metabolism and Interactions of Chloroquine and Hydroxychloroquine with Human Cytochrome P450 Enzymes and Drug Transporters.

BACKGROUND: In clinical practice, chloroquine and hydroxychloroquine are often co-administered with other drugs in the treatment of malaria, chronic inflammatory diseases, and COVID-19. Therefore, their metabolic properties and the effects on the activity of cytochrome P450 (P450, CYP) enzymes and drug transporters should be considered when developing the most efficient treatments for patients. METHODS: Scientific literature on the interactions of chloroquine and hydroxychloroquine with human P450 enzymes and drug transporters, was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/) and the ADME database (https://life-science.kyushu.fujitsu.com/admedb/). RESULTS: Chloroquine and hydroxychloroquine are metabolized by P450 1A2, 2C8, 2C19, 2D6, and 3A4/5 in vitro and by P450s 2C8 and 3A4/5 in vivo by N-deethylation. Chloroquine effectively inhibited P450 2D6 in vitro; however, in vivo inhibition was not apparent except in individuals with limited P450 2D6 activity. Chloroquine is both an inhibitor and inducer of the transporter MRP1 and is also a substrate of the Mate and MRP1 transport systems. Hydroxychloroquine also inhibited P450 2D6 and the transporter OATP1A2. CONCLUSIONS: Chloroquine caused a statistically significant decrease in P450 2D6 activity in vitro and in vivo, also inhibiting its own metabolism by the enzyme. The inhibition indicates a potential for clinical drug-drug interactions when taken with other drugs that are predominant substrates of the P450 2D6. When chloroquine and hydroxychloroquine are used clinically with other drugs, substrates of P450 2D6 enzyme, attention should be given to substrate-specific metabolism by P450 2D6 alleles present in individuals taking the drugs.

CYP17 inhibitors improve the prognosis of metastatic castration-resistant prostate cancer patients: A meta-analysis of published trials.

BACKGROUND AND AIMS: CYP17 inhibitors can block androgen production both intratumorally and systemically, thus attenuating the progression of prostate cancer (PCa). Many randomized controlled trials (RCTs) showed promising results that men with metastatic castration-resistant PCa (mCRPC) might benefit from treatment with CYP17 inhibitors such as abiraterone acetate and orteronel. The goal of this study was to evaluate the efficacy of CYP17 inhibitors for the prognosis in patients with mCRPC. MATERIALS AND METHODS: Studies were identified in PubMed/MEDLINE, the Cochrane Library, and the Web of Science. The RCTs with mCRPC patients focusing on the efficacy of CYP17 inhibitors were involved. Then, we analyzed the patients' prognosis such as overall survival (OS) and radiographic progression-free survival (RPFS). RESULTS: A meta-analysis of the pooled data from seven randomized Phase III clinical trials was performed to compare 5516 mCRPC patients with CYP17 inhibitors versus that with placebo. Compared to placebo, the CYP17 inhibitors significantly increased the OS (pooled hazard ratios [HR]: 0.816, 95% confidence interval [CI]: 0.750-0.887), RPFS (pooled HR: 0.647, 95% CI: 0.557-0.752), and time to prostate-specific antigen (PSA) progression (pooled HR: 0.599, 95% CI: 0.517-0.693). Additional endpoints such as PSA response rate, objective response assessed by Response Evaluation Criteria in Solid Tumors, and time to initiation of chemotherapy were included in this study and were found having significant improvement with CYP17 inhibitors compared to placebo. CONCLUSION: This research showed that CYP17 inhibitors had a significant improvement on prognosis of patients with mCRPC within a relative safety profile both in pre- and post-chemotherapy trials. These expected results provide evidence for the use of CYP17 inhibitors to treat mCRPCs.

Centrally administered CYP2D inhibitors increase oral tramadol analgesia in rats.

Cytochrome P450 2D (CYP2D) mediates the activation and inactivation of several classes of psychoactive drugs, including opioids, which can alter drug response. Tramadol is a synthetic opioid with analgesic activity of its own as well as being metabolically activated by CYP2D to O-desmethyltramadol (ODMST) an opioid receptor agonist. We investigated the impact of brain CYP2D metabolism on central tramadol and ODSMT levels, and resulting analgesic response after oral tramadol administration in rats. CYP2D inhibitors propranolol and propafenone were administered intracerebroventricularly prior to oral tramadol administration and analgesia was measured by tail-flick latency. Drug levels of tramadol and its metabolites, ODSMT and N-desmethyltramadol, were assessed in plasma and in brain by microdialysis using LC-ESI-MS/MS. Inhibiting brain CYP2D with propafenone pretreatment increased analgesia after oral tramadol administration (ANOVA p = 0.02), resulting in a 1.5-fold increase in area under the analgesia-time curve (AUC0-60, p < 0.01). This effect was associated with changes in the brain levels of tramadol and its metabolites consistent with brain CYP2D inhibition. In conclusion, under oral tramadol dosing pretreatment with a central administration of the CYP2D inhibitor propafenone increased analgesia (without altering plasma drug or metabolite levels), indicating that tramadol itself (and activity of CYP2D within the brain) contributed to analgesia.

Cancer stem cells and nanomedicine: new opportunities to combat multidrug resistance?

'Multidrug resistance' (MDR) is a difficult challenge for cancer treatment. The combined role of cytochrome P450 enzymes (CYPs) and active efflux transporters (AETs) in cancer cells appears relevant in inducing MDR. Chemotherapeutic drugs can be substrates of both CYPs and AETs and CYP inducers or inhibitors can produce the same effects on AETs. In addition, a small subpopulation of cancer stem-like cells (CSCs) appears to survive conventional chemotherapy, leading to recurrent disease. Natural products appear efficacious against CSCs; their combinational treatments with standard chemotherapy are promising for cancer eradication, in particular when supported by nanotechnologies.

Dried Leaf Artemisia Annua Improves Bioavailability of Artemisinin via Cytochrome P450 Inhibition and Enhances Artemisinin Efficacy Downstream.

Artemisia annua L. and artemisinin, have been used for millennia to treat malaria. We used human liver microsomes (HLM) and rats to compare hepatic metabolism, tissue distribution, and inflammation attenuation by dried leaves of A. annua (DLA) and pure artemisinin. For HLM assays, extracts, teas, and phytochemicals from DLA were tested and IC50 values for CYP2B6 and CYP3A4 were measured. For tissue distribution studies, artemisinin or DLA was orally delivered to rats, tissues harvested at 1 h, and blood, urine and feces over 8 h; all were analyzed for artemisinin and deoxyartemisinin by GC-MS. For inflammation, rats received an intraperitoneal injection of water or lipopolysaccharide (LPS) and 70 mg/kg oral artemisinin as pure drug or DLA. Serum was collected over 8 h and analyzed by ELISA for TNF-α, IL-6, and IL-10. DLA-delivered artemisinin distributed to tissues in higher concentrations in vivo, but elimination remained mostly unchanged. This seemed to be due to inhibition of first-pass metabolism by DLA phytochemicals, as demonstrated by HLM assays of DLA extracts, teas and phytochemicals. DLA was more effective than artemisinin in males at attenuating proinflammatory cytokine production; the data were less conclusive in females. These results suggest that the oral consumption of artemisinin as DLA enhances the bioavailability and anti-inflammatory potency of artemisinin.

Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds.

The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super complex critical for the electron transport chain. Herein we report the intracellular macrophage potency of nine diverse ITA analogs with MIC values ranging from 0.0625-2.5 µM and mono-drug resistant potency ranging from 0.0017 to 7 µM. The in vitro ADME properties (protein binding, CaCo-2, human microsomal stability and CYP450 inhibition) were determined for an outstanding compound of the series, ND-11543. ND-11543 was tolerable at >500 mg/kg in mice and at a dose of 200 mg/kg displayed good drug exposure in mice with an AUC(0-24h) >11,700 ng·hr/mL and a >24 hr half-life. Consistent with the phenotype observed with other QcrB inhibitors, compound ND-11543 showed efficacy in a chronic murine TB infection model when dosed at 200 mg/kg for 4 weeks. The efficacy was not dependent upon exposure, as pre-treatment with a known CYP450-inhibitor did not substantially improve efficacy. The ITAs are an interesting scaffold for the development of new anti-TB drugs especially in combination therapy based on their favorable properties and novel mechanism of action.

A hepatoprotection study of Radix Bupleuri on acetaminophen-induced liver injury based on CYP450 inhibition.

We investigated the potential hepatoprotective effect of Radix Bupleuri (RB) by inducing acute liver injury (ALI) in an animal model using acetaminophen (APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serumaspartate transaminase (AST) and alanine transaminase (ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine (APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione (GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2E1 and CYP3A activity. Further investigation revealed the increasing of CYP2E1 and CYP3A protein was significantly inhibited in pretreatment group, while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription.

Piperine Enhances the Antioxidant and Anti-Inflammatory Activities of Thymoquinone against Microcystin-LR-Induced Hepatotoxicity and Neurotoxicity in Mice.

Microcystin- (MC-) LR is the most frequent cyanotoxin produced by Microcystis aeruginosa cyanobacteria in the contaminated freshwater environment. MC represents a health hazard to humans and animals. Therefore, the present study was designed to evaluate the potential ameliorative effect of thymoquinone (TQ) and/or piperine (PP) against MC toxicity in mice. Fifty-six mice were randomly divided into seven experimental groups. Group I is the normal control that received distilled water for 21 days; Group II (TQ) was treated with TQ (10 mg/kg, i.p) for 21 days; Group III (PP) was treated with PP (25 mg/kg, i.p) for 21 days; Group IV (MC) was treated with MC (10 µg/kg, i.p) for 14 days and served as the toxic control; and Groups V, VI, and VII received TQ and/or PP 7 days prior to MC and continued for 14 days with MC. The results revealed that MC elicited hepatotoxicity and neurotoxicity which was evident due to the significant elevation of serum AST, ALT, γGT, ALP, LDH, IL-1ß, IL-6, and TNF-α levels. Furthermore, MC markedly increased MDA and NO contents along with reduction of GSH, SOD, CAT, and GSH-Px in liver and brain tissues. The electron transport chain may be a possible target for MC. TQ and/or PP ameliorated the MC-mediated oxidative damage in the liver and brain which might be attributed to their antioxidant properties. However, the concurrent treatment of TQ and PP showed the best regimen as a result of the PP-enhanced bioavailability of TQ.

Carvacrol inhibits cytochrome P450 and protects against binge alcohol-induced liver toxicity.

Alcoholism is a serious addiction that can lead to various health complications such as liver fibrosis, steatosis, and cirrhosis. Carvacrol is present in many plant-based essential oils and used as a preservative in the food industry. In this study, we have investigated the hepatoprotective role of carvacrol against ethanol-induced liver toxicity in mice. To determine the effect of carvacrol on liver injury parameters, 5 doses of 50% ethanol (10 mL/kg body weight) were orally administered every 12 h for inducing the hepatotoxicity in experimental mice. Interestingly, carvacrol pre-treatment (50 and 100 mg/kg) reversed the ethanol-induced effects on liver function, antioxidant markers, matrix metalloproteinases activities, and histological changes. Moreover, carvacrol binds to the active pocket of cytochrome P450 (Cyt P450) and inhibits its expression. Thus, our finding suggests carvacrol can be used as an adjuvant for the amelioration of alcohol-induced hepatotoxicity.

A Novel Orally Active Inverse Agonist of Estrogen-related Receptor Gamma (ERRγ), DN200434, A Booster of NIS in Anaplastic Thyroid Cancer.

PURPOSE: New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy-refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRγ) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC50 = 0.006 µmol/L), selective, and orally available ERRγ inverse agonist for NIS enhancement in ATC. EXPERIMENTAL DESIGN: We sought to identify better ERRγ-targeting ligands and explored the crystal structure of ERRγ in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression, as well as radioiodine avidity was examined. ATC tumor-bearing mice were orally administered with DN200434, followed by 124I-positron emission tomography/CT (PET/CT). For radioiodine therapy, ATC tumor-bearing mice treated with DN200434 were administered 131I (beta ray-emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histologic analysis was performed to evaluate ERRγ expression status in normal tissue and ATC tissue, respectively. RESULTS: DN200434-ERRγ complex crystallographic studies revealed that DN200434 binds to key ERRγ binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by 124I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histologic findings of patients with ATC showed higher ERRγ expression in tumors than in normal tissue, supporting ERRγ as a therapeutic target for ATC. CONCLUSIONS: DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.

Pharmacological Utilization of Bergamottin, Derived from Grapefruits, in Cancer Prevention and Therapy.

Cancer still remains one of the leading causes of death worldwide. In spite of significant advances in treatment options and the advent of novel targeted therapies, there still remains an unmet need for the identification of novel pharmacological agents for cancer therapy. This has led to several studies evaluating the possible application of natural agents found in vegetables, fruits, or plant-derived products that may be useful for cancer treatment. Bergamottin is a furanocoumarin derived from grapefruits and is also a well-known cytochrome P450 inhibitor. Recent studies have demonstrated potent anti-oxidative, anti-inflammatory, and anti-cancer properties of grapefruit furanocoumarin both in vitro and in vivo. The present review focuses on the potential anti-neoplastic effects of bergamottin in different tumor models and briefly describes the molecular targets affected by this agent.

Targeting cytochrome P450-dependent cancer cell mitochondria: cancer associated CYPs and where to find them.

While cytochrome P450 (CYP)-mediated biosynthesis of arachidonic acid (AA) epoxides promotes tumor growth by driving angiogenesis, cancer cell intrinsic functions of CYPs are less understood. CYP-derived AA epoxides, called epoxyeicosatrienoic acids (EETs), also promote the growth of tumor epithelia. In cancer cells, CYP AA epoxygenase enzymes are associated with STAT3 and mTOR signaling, but also localize in mitochondria, where they promote the electron transport chain (ETC). Recently, the diabetes drug metformin was found to inhibit CYP AA epoxygenase activity, allowing the design of more potent biguanides to target tumor growth. Biguanide inhibition of EET synthesis suppresses STAT3 and mTOR pathways, as well as the ETC. Convergence of biguanide activity and eicosanoid biology in cancer has shown a new pathway to attack cancer metabolism and provides hope for improved treatments that target this vulnerability. Inhibition of EET-mediated cancer metabolism and angiogenesis therefore provides a dual approach for targeted cancer therapeutics.

Prospective for cytochrome P450 epoxygenase cardiovascular and renal therapeutics.

Therapeutics for arachidonic acid pathways began with the development of non-steroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX). The enzymatic pathways and arachidonic acid metabolites and respective receptors have been successfully targeted and therapeutics developed for pain, inflammation, pulmonary and cardiovascular diseases. These drugs target the COX and lipoxygenase pathways but not the third branch for arachidonic acid metabolism, the cytochrome P450 (CYP) pathway. Small molecule compounds targeting enzymes and CYP epoxy-fatty acid metabolites have evolved rapidly over the last two decades. These therapeutics have primarily focused on inhibiting soluble epoxide hydrolase (sEH) or agonist mimetics for epoxyeicosatrienoic acids (EET). Based on preclinical animal model studies and human studies, major therapeutic indications for these sEH inhibitors and EET mimics/analogs are renal and cardiovascular diseases. Novel small molecules that inhibit sEH have advanced to human clinical trials and demonstrate promise for cardiovascular diseases. Challenges remain for sEH inhibitor and EET analog drug development; however, there is a high likelihood that a drug that acts on this third branch of arachidonic acid metabolism will be utilized to treat a cardiovascular or kidney disease in the next decade.

Effect of valproic acid on perampanel pharmacokinetics in patients with epilepsy.

We prospectively examined the effect of antiepileptic (AED) cotherapy on steady state plasma concentrations of perampanel (PMP) in epileptic patients. We classified AEDs as strong enzyme inducers (carbamazepine, phenobarbital, phenytoin, oxcarbazepine), not strong enzyme inducers/not inhibitors (levetiracetam, lamotrigine, topiramate, rufinamide, lacosamide, zonisamide, clobazam), and enzyme inhibitors (valproic acid [VPA]). The main outcome was the comparison of PMP plasma concentration to weight-adjusted dose ratio (C/D; [µg/mL]/mg kg-1  d-1 ) among comedication subgroups. From 79 patients (42 females, 37 males) aged (mean ± standard deviation) 33 ± 13 years (range = 12-66 years), 114 plasma samples were collected. Twenty-eight patients (44 samples) were cotreated with enzyme inducers (group A), 21 (27 samples) with not strong enzyme inducers/not inhibitors (group B), 21 (31 samples) with not strong enzyme inducers/not inhibitors + VPA (group C), and 9 (12 samples) with enzyme inducers + VPA (group D). PMP C/D was reduced (-56%, P < .001) in group A (1.79 ± 0.80) versus group B (4.05 ± 2.16) and increased (P < .001) in group C (6.72 ± 4.04) compared with groups A (+275%), B (+66%), and D (2.76 ± 2.00, +143%). Our study documents the unpublished higher PMP C/D in patients cotreated with VPA. These findings have both theoretical relevance, suggesting better characterization of PMP metabolic pathways with ad hoc studies, and clinical usefulness in managing patients on AED polytherapy.