Cytochrome P450 Inhibition Potential Research Articles

Optimization of assay conditions to quantify ECOD activity in vivo in individual Daphnia magna. Assay performance evaluation with model CYP 450 inducers/inhibitors

Screening the activity of the cytochrome P450 (CYP450) mixed function oxidase system in aquatic invertebrates received seldom applications in ecotoxicology due to low baseline enzymatic activities characteristic for these organisms. In this study, an existing in vivo spectrofluorometric assay method based on quantifying the cytochrome P450 mediated conversion of 7-ethocycoumarin (EtC) used as substrate to the product 7-hydroxycoumarin (HCm) called: ethoxycoumarin-O-deethylase (ECOD) activity, initially applicable on pooled samples of Daphnia magna, was optimized for use on individual organisms. Optimal assay conditions have been established for as small as 3- and 6 days old individuals, and the limits of spectrofluorometric detection of HCm excreted by daphnids in the incubation media were defined. The modified assay was tested by screening the modulation of ECOD activity in daphnids following 24 h exposure to β-naphthoflavone (β-NF, reference CYP450 inducer) and to prochloraz (PCZ), a potent CYP450 inhibitor. Maximal ECOD activity levels in daphnids were recorded following 2 hours of incubation to 200 nM EtC. The limit of spectrofluorometric detection of HCm in the incubation media was 6.25 nM, achieved by more than 80% of three days old daphnids and all six days old individuals. Exposure of daphnids to β-NF demonstrated a bell-shaped ECOD activity induction potential, while PCZ elicited partial (60%) inhibition of ECOD activity. This optimized in vivo ECOD activity assay may serve as a cost-effective tool to study the responsiveness of Phase-I metabolism in D. magna to toxic pressure and its applicability to other aquatic invertebrates is also worth for consideration.

Physiologically Based Pharmacokinetic Modeling of Quinidine to Establish a CYP3A4, P-gp and CYP2D6 Drug-Drug-Gene Interaction Network.

The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) and is therefore recommended for use in clinical drug-drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P-gp, it is susceptible to DDIs involving these proteins. Physiologically based pharmacokinetic (PBPK) modeling can help to mechanistically assess the absorption, distribution, metabolism, and excretion (ADME) processes of a drug and has proven its usefulness in predicting even complex interaction scenarios. The objectives of the presented work were to develop a PBPK model of quinidine and to integrate the model into a comprehensive drug-drug(-gene) interaction (DD(G)I) network with a diverse set of CYP3A4 and P-gp perpetrators as well as CYP2D6 and P-gp victims. The quinidine parent-metabolite model including 3-hydroxyquinidine was developed using pharmacokinetic profiles from clinical studies after intravenous and oral administration covering a broad dosing range (0.1-600 mg). The model covers efflux transport via P-gp and metabolic transformation to either 3-hydroxyquinidine or unspecified metabolites via CYP3A4. The 3-hydroxyquinidine model includes further metabolism by CYP3A4 as well as an unspecific hepatic clearance. Model performance was assessed graphically and quantitatively with >90% of predicted pharmacokinetic parameters within two-fold of corresponding observed values. The model was successfully used to simulate various DD(G)I scenarios with >90% of predicted DD(G)I pharmacokinetic parameter ratios within two-fold prediction success limits. The presented network will be provided to the research community and can be extended to include further perpetrators, victims and targets, to support investigations of DD(G)Is.

Orbital myeloid sarcoma treated with low-dose venetoclax and a potent cytochrome P450 inhibitor.

We report the first case of orbital myeloid sarcoma that was successfully treated with a standard venetoclax dose of 25%. A 38-year-old man with acute myeloid leukemia (AML) post-haplo-hematopoietic stem cell transplantation (HSCT) presented with a nine-month history of progressive right proptosis and a visual acuity deficit. The patient was treated with venetoclax (100 mg orally on days 1-28), cytarabine (40 mg subcutaneously, days 1-10), and itraconazole (100 mg twice daily orally on days 1-28). The present case report shows that using cytochrome P450 (CYP) inhibitors is a helpful strategy to reduce the cost of expensive treatments. There are limited data on the use of CYP inhibitors as a strategy to reduce the costs of expensive drugs (i.e. venetoclax). This approach has some advantages over standard dose venetoclax (400 mg/day) such as significantly reduced costs (which is relevant for patients in low-income countries). In this case, we used itraconazole-a potent CYP3A4 inhibitor-which can theoretically reduce the dose to 100 mg/day without losing serum therapeutic concentrations.

Do Inhibitory Metabolites Impact DDI Risk Assessment? Analysis of in vitro and in vivo Data from NDA Reviews Between 2013 and 2018.

Evaluating the potential of new drugs and their metabolites to cause drug-drug interactions (DDIs) is critical for understanding drug safety and efficacy. Although multiple analyses of proprietary metabolite testing data have been published, no systematic analyses of metabolite data collected according to current testing criteria have been conducted. To address this knowledge gap, 120 new molecular entities approved between 2013 and 2018 were reviewed. Comprehensive data on metabolite-to-parent area under the curve ratios (AUCM /AUCP ), inhibitory potency of parent and metabolites, and clinical DDIs were collected. Sixty-four percent of the metabolites quantified in vivo had AUCM /AUCP ≥0.25 and 75% of these metabolites were tested for cytochrome P450 (CYP) inhibition in vitro, resulting in 15 metabolites with potential DDI risk identification. Although 50% of the metabolites with AUCM /AUCP <0.25 were also tested in vitro, none of them showed meaningful CYP inhibition potential. The metabolite percentage of plasma total radioactivity cutoff of ≥10% did not appear to add value to metabolite testing strategies. No relationship between metabolite versus parent drug polarity and inhibition potency was observed. Comparison of metabolite and parent maximum concentration (Cmax ) divided by inhibition constant (Ki ) values suggested that metabolites can contribute to in vivo DDIs and, hence, quantitative prediction of clinical DDI magnitude may require both parent and metabolite data. This systematic analysis of metabolite data for newly approved drugs supports an AUCM /AUCP cutoff of ≥0.25 to warrant metabolite in vitro CYP screening to adequately characterize metabolite inhibitory DDI potential and support quantitative DDI predictions.

Cytochrome P450 inhibition potential and initial genotoxic evaluation of 14-O-[(4,6-diaminopyrimidine-2-yl)thioacetyl] mutilin

14-O-[(4,6-Diaminopyrimidine-2-yl)thioacetyl] mutilin (DPTM) is a promising drug candidate with excellent antibacterial activity against Gram-positive bacteria. The present study was designed to characterize its Cytochrome P450 (CYP) enzymes inhibition activities and the genotoxicity with the standard Ames test. We determined the inhibitory effects of DPTM on CYP1A2, CYP2D1/6, CYP2E1, CYP2C11/9 and CYP3A/4 in rat liver microsomes (RLMs) and in human liver microsomes (HLMs). The mRNA expressions of the above CYP isoforms and their transcriptional regulators were also evaluated using the Hep G2 cell model. The results showed DPTM exhibited a moderate inhibitory potential against CYP3A/4 (IC50 values of 10 ± 2 and 8 ± 2 μM, respectively) and weak against the other CYP enzymes based on their IC50 values. Compared to the control, CYP isoforms and their transcriptional regulators mRNA expressions significantly increased when the Hep G2 cells were treated with DPTM for a certain period of time. In the Ames test, Salmonella strains TA97, TA98, TA100, TA102 and TA1535 were treated with or without the metabolic activation (S9). Analysis showed the average number of revertant colonies per plate was less in double in the groups treated with DPTM than that in the negative control plate and showed no dose-related increase.

Preventing Cushing: Iatrogenic Cushing Syndrome due to Ritonavir-Fluticasone Interaction

Ritonavir is commonly used in low doses to boost plasma levels of protease inhibitors in patients with human immunodeficiency virus (HIV) infections. It is also a potent inhibitor of cytochrome P450. We present a 50-year-old African American male with past medical history of HIV on highly active antiretroviral therapy (HAART), which also included ritonavir and long standing asthma that has been treated with inhaled fluticasone, who presented with back pain. He had central obesity, prominent abdominal striae and wasted extremities on physical examination. Laboratory tests showed low morning serum cortisol and suboptimal cosyntropin test consistent with adrenal insufficiency. Computed tomography (CT) of the spine showed a fracture of inferior endplate of the lumbar (L3) vertebra. The cause of osteoporosis is believed to be iatrogenic Cushing syndrome caused by enhanced levels of inhaled fluticasone effects secondary to inhibition of cytochrome P450. The patient was managed surgically and fluticasone was discontinued.

Adverse Effects, Expression of the Bk-CYP3045C1 Gene, and Activation of the ERK Signaling Pathway in the Water Accommodated Fraction-Exposed Rotifer.

To examine the deleterious effects of the water accommodated fraction (WAF) of crude oil, the growth curve, fecundity, and lifespan of the monogonont rotifer (Brachionus koreanus) were measured for 24 h in response to three different doses (0.2×, 0.4×, and 0.8×) of WAFs. A higher dose of WAFs significantly reduced the fecundity and lifespan. A rotifer 32K microarray chip showed that the Bk-CYP3045C1 gene had the highest expression. Of the 25 entire CYP genes, the Bk-CYP3045C1 gene showed a significant expression for different doses and times in response to WAFs and chemical components of WAFs (naphthalene and phenanthrene); also, glutathione S-transferase genes, ABC transporter, and other genes showed dose responses upon exposure to 80% WAF over time. Different doses of WAFs increased the oxidative stress with an induction of reactive oxygen species (ROS) and a depletion of glutathione (GSH). Exposure to WAFs did not show toxic effects on survivability in B. koreanus; however, toxicity to WAFs was shown when piperonyl butoxide, a potent inhibitor of cytochrome P450 (CYP) enzymes, was added. This toxicity was dose-dependent. After WAFs exposure, p-ERK was activated over time in response to WAFs, which suggests that WAFs can be activated by the p-ERK signaling pathway.

Understanding Oxadiazolothiazinone Biological Properties: Negative Inotropic Activity versus Cytochrome P450-Mediated Metabolism.

We present a series of oxadiazolothiazinones, selective inotropic agents on isolated cardiac tissues, devoid of chronotropy and vasorelaxant activity. Functional and binding data for the precursor of the series (compound 1) let us hypothesize LTCC blocking activity and the existence of a recognition site specific for this scaffold. We synthesized and tested 22 new derivatives: introducing a para-methoxyphenyl at C-8 led to compound 12 (EC50 = 0.022 μM), twice as potent as its para-bromo analogue (1). For 10 analogues, we extended the characterization of the biological properties by including the assessment of metabolic stability in human liver microsomes and cytochrome P450 inhibition potential. We observed that the methoxy group led to active compounds with low metabolic stability and high CYP inhibition, whereas the protective effect of bromine resulted in enhanced metabolic stability and reduced CYP inhibition. Thus, we identified two para-bromo benzothiazino-analogues as candidates for further studies.

Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class.

New psychoactive substances (NPS) are not tested for their cytochrome P450 (CYP) inhibition potential before consumption. Therefore, this potential was explored for tryptamine-derived NPS (TDNPS) including alpha-methyl tryptamines (AMTs), dimethyl tryptamines (DMTs), diallyl tryptamines (DALTs), and diisopropyl tryptamines (DiPTs) using test substrates preferred by the Food and Drug Administration in a cocktail assay. All tested TDNPS with the exception of DMT inhibited CYP2D6 activity with IC50 values below 100μM. DALTs inhibited CYP2D6 activity similar to paroxetine and quinidine and CYP1A2 activity comparable to fluvoxamine. 5-Methoxy-N,N-diallyltryptamine reduced in vivo the caffeine metabolism in rats consistent with in vitro results. Five of the AMTs also inhibited CYP1A2 activity comparable to amiodarone. AMT and 6-F-AMT inhibited CYP2A6 activity in the range of the test inhibitor tranylcypromine. CYP2B6 activity was inhibited by 19 tryptamines, but weakly compared to efavirenz. CYP2C8 activity was inhibited by five of the tested TDNPS and three showed values comparable to trimethoprim and gemfibrozil. Six tryptamines inhibited CYP2C9 and seven CYP2C19 activities comparable to fluconazole and chloramphenicol, respectively. Nineteen compounds showed inhibition of CYP2E1 and 18 of CYP3A activity, respectively. These results showed that the CYP inhibition by TDNPS might be clinically relevant, but clinical studies are needed to explore this further.

Impact and differential clinical utility of cobicistat-boosted darunavir in HIV/AIDS

Impact and differential clinical utility of cobicistat-boosted darunavir in HIV/AIDS Maria Vittoria Cossu, Noemi Astuti, Amedeo Capetti, Giuliano Rizzardini1st Division of Infectious Diseases, Luigi Sacco University Hospital, Milan, ItalyAbstract: Cobicistat (Cobi) is a pharmacoenhancer, without anti-HIV activity, that optimizes systemic exposures of protease inhibitors (PIs) such as atazanavir (ATV) and darunavir (DRV). In particular, Cobi is a potent inhibitor of cytochrome P450 (CYP) 3A enzymes, the main metabolizing pathway of this class of antiretrovirals. Due to its more selective inhibition of CYP3A, Cobi has a lower potential for off-target drug interactions than the standard boosting agent ritonavir (RTV), and lower likelihood for enzymatic induction. In pharmacokinetic studies of healthy volunteers, DRV boosted with Cobi attains plasma concentrations that are comparable to those achieved with 100 mg RTV as booster. In Phase III clinical trials, conducted in na&iuml;ve subjects, the coformulation yielded high rates of suppression of viral replication, on average 82%&ndash;83% of treated patients reaching undetectable viremia after 48 weeks of therapy. The selection of resistance associated with mutations was a rare event and no phenotypic resistance to DRV emerged in viral failures. Generally, Cobi was well tolerated; however, it has been shown to decrease estimated creatinine clearance (ClCr) due to inhibition of tubular secretion of creatinine. Cobi, therefore, should not be initiated in patients with ClCr less than 70 mL/min, if any coadministered agent (eg, emtricitabine, lamivudine, tenofovir disoproxil fumarate, or adefovir) requires dose adjustment based on ClCr.DRV/Cobi fixed-dose combination is part of an important evolution of antiretroviral therapy toward simpler yet potent formulations. In this setting, it is important to combine potency, simplicity, safety, and high genetic barrier, as in this case.Keywords: HIV, darunavir, Cobicistat, fixed dose, pharmacoenhancer

In vitro cytochrome P450 inhibition potential of methylenedioxy-derived designer drugs studied with a two-cocktail approach.

In vitro cytochrome P450 (CYP) inhibition assays are common approaches for testing the inhibition potential of drugs for predicting potential interactions. In contrast to marketed medicaments, drugs of abuse, particularly the so-called novel psychoactive substances, were not tested before distribution and consumption. Therefore, the inhibition potential of methylenedioxy-derived designer drugs (MDD) of different drug classes such as aminoindanes, amphetamines, benzofurans, cathinones, piperazines, pyrrolidinophenones, and tryptamines should be elucidated. The FDA-preferred test substrates, split in two cocktails, were incubated with pooled human liver microsomes and analysed after protein precipitation using LC-high-resolution-MS/MS. IC50 values were determined of MDD showing more than 50% inhibition in the prescreening. Values were calculated by plotting the relative metabolite concentration formed over the logarithm of the inhibitor concentration. All MDD showed inhibition against CYP2D6 activity and most of them in the range of the clinically relevant CYP2D6 inhibitors quinidine and fluoxetine. In addition, the beta-keto compounds showed inhibition of the activity of CYP2B6, 5,6-MD-DALT of CYP1A2 and CYP3A, and MDAI of CYP2A6, all in the range of clinically relevant inhibitors. In summary, all MDD showed inhibition of the activity of CYP2D6, six of CYP1A2, three of CYP2A6, 13 of CYP2B6, two of CYP2C9, six of CYP2C19, one of CYP2E1, and six of CYP3A. These results showed that the CYP inhibition by MDD might be clinically relevant, but further studies are needed for final conclusions.

759PD - Ar and Cyp17A1 Copy Number Variations May Predict Clinical Outcome of Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone

ABSTRACT Aim: Abiraterone acetate is a potent inhibitor of cytochrome P450 17 alpha-hydrolase (CYP17A1) causing decrease of synthesis of testosterone in the adrenal glands, testicles and tumor microenvironment with survival advantage in patients with metastatic castration-resistant prostate cancer (CRPC). We analyzed the predictive role of copy number variations (CNVs) of CYP17A1 and androgen receptor (AR) genes, in serum cell free DNA of CRPC patients treated with abiraterone. Patients and methods: The study was conducted on a consecutive series of 53 CRPC patients treated with abiraterone after at least one chemotherapeutic regimen with docetaxel. DNA was isolated from serum collected before starting abiraterone treatment and CNVs were analyzed for AR and CYP17A1 genes using Taqman copy number assays. Results: AR gene resulted amplified in 16 cases, CYP17A1 in 15. 10 cases were amplified for both genes. The median progression-free survival (PFS) of patients with AR gene amplification was 2.8 vs. 9.5 months of normal individuals. Patients with CYP17A1 gene amplification had a median PFS of 2.8 months vs. 9.2 months in the diploid patients. A lower overall survival (OS) was reported in patients with AR and CYP17A1 gene amplification (AR: P Conclusions: The CNVs of AR and CYP17A1 genes are promising markers predicting outcome in patients with CRPC treated with abiraterone. Further studies are warranted to validate these biomarkers to be used through a “liquid biopsy”, for outcome prediction to abiraterone in these patients. Disclosure: All authors have declared no conflicts of interest.

Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479

Use of the tools of SBDD including crystallography led to the discovery of novel and potent 6,5 heterobicyclic MEKi’s [J. Med. Chem.2012, 55, 4594]. The core change from a 5,6 heterobicycle to a 6,5 heterobicycle was driven by the desire for increased structural diversity and aided by the co-crystal structure of G-925 [J. Med. Chem.2012, 55, 4594]. The key design feature was the shift of the attachment of the five-membered heterocyclic ring towards the B ring while maintaining the key hydroxamate and anilino pharamcophoric elements in a remarkably similar position as in G-925. From modelling, changing the connection point of the five membered ring heterocycle placed the H-bond accepting nitrogen within a good distance and angle to the Ser212 [J. Med. Chem.2012, 55, 4594]. The resulting novel 6,5 benzoisothiazole MEKi G-155 exhibited improved potency versus aza-benzofurans G-925 and G-963 but was a potent inhibitor of cytochrome P450’s 2C9 and 2C19. Lowering the logD by switching to the more polar imidazo[1,5-a] pyridine core significantly diminished 2C9/2C19 inhibition while retaining potency. The imidazo[1,5-a] pyridine G-868 exhibited increased potency versus the starting point for this work (aza-benzofuran G-925) leading to deprioritization of the azabenzofurans. The 6,5-imidazo[1,5-a] pyridine scaffold was further diversified by incorporating a nitrogen at the 7 position to give the imidazo[1,5-a] pyrazine scaffold. The introduction of the C7 nitrogen was driven by the desire to improve metabolic stability by blocking metabolism at the C7 and C8 positions (particularly the HLM stability). It was found that improving on G-868 (later renamed GDC-0623) required combining C7 nitrogen with a diol hydroxamate to give G-479. G-479 with polarity distributed throughout the molecule was improved over G-868 in many aspects.

Adrenal Enzyme Impairment in Neonates and Adolescents Treated with Ritonavir and Protease Inhibitors for HIV Exposure or Infection

Background: Human deficiency virus (HIV) protease inhibitors (PIs) are widely used drugs whose effects are pharmacologically enhanced by ritonavir, a potent cytochrome P450 inhibitor. We reported previously that prophylactic postnatal ritonavir-PI therapy in HIV-exposed neonates was associated with increases in plasma 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulfate (DHEA-S). Aims: To further investigate adrenal function in neonates and adolescents given ritonavir-PI. Methods: Adrenal function was assessed prospectively in 3 HIV-exposed neonates given short-term prophylactic treatment and 3 HIV-infected adolescents given long-term treatment. Plasma cortisol, 17-OHP, 17-OH-pregnenolone, DHEA-S, and androstenedione were measured before and after ACTH administration. Results: None of the patients had clinical signs of adrenal dysfunction. The only neonate exposed to ritonavir-PI in utero had up to 3-fold increases in plasma 17-OHP. Increases in 17-OH-pregnenolone of up to 3.1-fold were noted in 4 of the 6 patients, and all 6 patients had elevations in DHEA-S (up to 20.4-fold increase) and/or DHEA (up to 4.7-fold) and/or androstenedione (up to 5.2-fold). All these parameters improved after treatment completion. Conclusion: Neonates and adolescents given ritonavir-PI exhibit a similar adrenal dysfunction profile consistent with an impact on multiple adrenal enzymes. These abnormalities require evaluation, given the potentially long exposure times.

Triamcinolone and ritonavir leading to drug-induced Cushing syndrome and adrenal suppression: description of a new case and review of the literature

The protease inhibitor (PI) ritonavir is a potent inhibitor of cytochrome P450 (CYP) 3A4 activity and frequently prescribed to boost the effectiveness of other PIs as part of highly active antiretroviral therapy. It is well established that ritonavir is capable of inducing iatrogenic Cushing syndrome (ICS) through a drug-drug interaction with inhaled fluticasone that leads to the inhibition of CYP3A activity. A rapidly increasing number of case reports are being published describing ICS induced by the interaction of ritonavir and injected corticosteroids, namely triamcinolone acetonide. A review of the current literature identified 15 cases (including the one reported here) of ICS and suppression of the hypothalamic-pituitary-adrenal axis after periradicular injection of triamcinolone acetonide. Considering an aging human immunodeficiency virus (HIV)-infected population an increasing number of patients will present with degenerative musculoskeletal disease and be seeking pain relief. Based on data reported in the literature and our own experience triamcinolone injections during ritonavir-based therapy should be avoided. After failure of all conservative therapeutic options methylprednisolone may represent a therapeutic alternative for steroid injections in HIV patients receiving PI-based antiviral therapy since it has to date not been associated with ICS.

Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists

Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats.

Pitavastatin Concentrations Are Not Increased by CYP3A4 Inhibitor Itraconazole in Healthy Subjects.

Itraconazole is a synthetic triazole antifungal agent which is known to be a potent inhibitor of cytochrome P450 (CYP) 3A4, and may cause drug-drug interactions with the many drugs metabolized by this route, including some statins. In this study, the influence of concomitant administration of a single oral dose of pitavastatin with itraconazole at steady state was investigated to determine the potential for pharmacokinetic interaction and any effects on safety. Eighteen subjects were enrolled into the study. The AUC and Cmax of pitavastatin alone were 138 ng h/mL and 63.8 ng/mL, and pitavastatin with itraconazole were 106 ng h/mL and 49.5 ng/mL, respectively. Comparison of the 90% confidence interval of the geometric mean ratio of AUC0-t and Cmax against a standard reference of 0.80-1.25 demonstrated that the lower limit was breached for both pitavastatin and its lactone metabolite (0.71-0.84 and 0.69-0.88 for AUC0-t and Cmax , respectively, for pitavastatin, 0.86-0.97 and 0.76-0.86 for AUC0-t and Cmax , respectively, for pitavastatin lactone). The safety and tolerability of pitavastatin was not affected by co-administration with itraconazole. This study suggests that pitavastatin is not a CYP3A4 substrate in humans.

Computer-aided design of selective Cytochrome P450 inhibitors and docking studies of alkyl resorcinol derivatives

The present investigation is aimed to understand the interactive mechanism that occurs between the active site of Cytochrome P450 and its inhibitors by molecular modeling studies. Based on the docking studies and information obtained from interaction analysis, structure-based virtual screening was performed by selecting 217 new potential inhibitors with structural diversity using GOLD and ArgusLab molecular docking softwares. Among a total of 217 compounds, only 21 molecules were considered as the potential inhibitors. Hydrogen bond and van der Waals interaction between various active site residues like ARG 382, HIS447, CYS449, ASN493, TYR131, and TYR92 of Cytochrome P450 were observed. Docking studies of selected resorcinols showed an optimal molecular environment which is required to bind with active sites of Cytochrome P450. Hydroxyl groups of resorcinols exhibited van der Waals interactions with certain active sites. To estimate the drug-likeness properties the parameters like partition coefficient (log P), tabulated molecular polar surface area (TPSA), and bio activity score were obtained from the Molinspiration studies. Based on docking and Molinspiration data analysis, the molecules 10, 3, 18, 19, and 7 were found to be highly potent inhibitors of Cytochrome P450.

Augmentation of Venlafaxine With Bupropion

Article AbstractIn patients who show partial response to venlafaxine, augmentation with a second antidepressant may be considered with bupropion as a candidate drug. Theoretically, the advantage of the venlafaxine-bupropion combination is that it results in the reuptake inhibition of serotonin and norepinephrine, as well as dopamine; such a triple neurotransmitter reuptake inhibition formula could be expected to maximize the chances of treatment response. However, there are pharmacokinetic risks associated with this antidepressant combination because bupropion is a potent inhibitor of cytochrome P450 (CYP) 2D6, the enzyme responsible for the metabolism of venlafaxine. Bupropion can substantially raise venlafaxine levels, resulting in a variety of dose-dependent serotonergic and noradrenergic adverse effects, ranging from increased anxiety and restlessness to increased blood pressure. Coping with the interaction requires awareness of the risk of such an interaction, knowledge about dose-dependent serotonergic and noradrenergic adverse effects of antidepressant drugs, down-titration of the dose of venlafaxine (or temporary withdrawal of the drug) should such adverse effects emerge during combination treatment, and the use of blood levels of venlafaxine and desvenlafaxine as a guide in down-titration, should facilities for such estimations be available. Fortunately, although venlafaxine and its active metabolite desvenlafaxine mildly inhibit CYP2D6, these drugs do not increase bupropion levels, because CYP2D6 is not involved in the metabolism of bupropion.

Statin Muscle Toxicity and Genetic Risk Factors

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) can cause skeletal muscle toxicity; the risk of toxicity is elevated by drug interactions and pharmacogenetic factors that increase the concentration of statins in plasma. The genetic basis of statin-related muscle disorders is largely unknown. Statins are substrates for several membrane transporters that may mediate drug interactions. Potent inhibitors of cytochrome P450 (CYP450) especially CYP3A4, can significantly increase the plasma concentrations of the active forms of atorvastatin, lovastatin and simvastatin. Fluvastatin, which is metabolized by CYP2C9, is less prone to pharmacokinetic interactions, while pravastatin and rosuvastatin are not susceptible to any CYP inhibition. OATP1B1 can decrease the hepatic uptake of many statins, as well as the therapeutic index of these agents. Polymorphisms of CYP450 enzymes, SLCO1B1, ABCB1, and COQ2 gene, can induce statin intolerance. This review summarized the principal relations known between statin myotoxicity and genetic risk factors.