CYP Isoenzymes Research Articles

Identification of novel diarylpyrimidine derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against wild-type and K103N mutant viruses

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a crucial role in combination antiretroviral therapy (cART). To further enhance their antiviral activity and anti-resistance properties, we developed a series of novel NNRTIs, by specifically targeting tolerant region I of the NNRTI binding pocket. Among them, compound 9t-2 displayed excellent anti-HIV-1 potency against wild-type and prevalent mutant strains with EC50 values between 0.0019 and 0.012 μM. This outperformed the positive drugs ETR, NVP and RPV. Aslo, ELISA results confirmed that these compounds can effectively inhibit the activity of HIV-1 RT. Molecular dynamics (MD) simulation studies indicated that the thiomorpholine-1,1-dioxide moiety of 9t-2 is capable of establishing additional interactions with residues P225, F227 and P236 in the tolerant region I, which contributed to its enhanced activity. Compound 9t-2 possessed negligible inhibitory effect on the five main CYP isoenzymes (IC50 > 10 μM), indicating a low potential for inducing CYP-mediated drug-drug interactions. In conclusion, compound 9t-2, with its enhanced anti-resistance properties, stands out as a promising lead compound for further optimization towards discovering the new generation of anti-HIV agents.

Herb-drug interaction study of Yiqi Fumai lyophilized injection (YQFM) on pharmacokinetics of aspirin, nifedipine, and clopidogrel in rats.

Yiqi Fumai lyophilized injection (YQFM), a compound traditional Chinese medicine prescription derived from "Sheng Mai Powder," is approved for the treatment of cardiovascular diseases. YQFM is usually prescribed in combination with some Western medicines to treat patients, such as aspirin, nifedipine, and clopidogrel. However, the herb-drug interactions (HDIs) of YQFM are still unclear. We determined the effect of YQFM on drug metabolism-related CYP450 enzymes by in vitro assays. And the effects of YQFM on the pharmacokinetics of aspirin, nifedipine, or clopidogrel were analyzed in rats, as well as the effect of YQFM on the prothrombin time of aspirin or clopidogrel, to evaluate the safety and efficacy of co-administration. Our study indicated that the clinical dose of YQFM did not significantly influence the relevant CYP450 isoenzymes. Besides, YQFM had no effect on the pharmacokinetics of aspirin, nifedipine, or clopidogrel single and multiple administrations in rats. In pharmacodynamics study, YQFM also had no impact on prothrombin time of aspirin or clopidogrel. Based on the results of pharmacogenomics, pharmacokinetics, and pharmacodynamics, the HDIs of YQFM have a good safety profile, and the combination with the above three drugs might have synergistic effects due to the different efficacy of YQFM-quality markers.

Physicochemical analysis of chitosan oligosaccharide revealed its usefulness in effective delivery of drugs

Chitosan oligosaccharides are biopolymers with a wide range of potential applications in various fields. This biopolymer is diverse and promising, and current research is investigating its capabilities for improved drug delivery. As chitosan oligosaccharide has the potential to be used as a drug delivery option, the purpose of this study was to examine its physicochemical characteristics and its potential for drug delivery. In this study, the pharmacokinetic properties of chitosan oligosaccharide were studied through Insilco investigation, which revealed that it is an extremely soluble and effective drug delivery candidate because it does not inhibit CYP isoenzymes and has a log Kp of −12.10 cm/s. It belongs to toxicity class 6 for acute oral toxicity, with an average similarity of 87.5% and a prediction accuracy of 70.97%. Additionally, XRD peak analysis revealed that the material was amorphous, as the peak appeared at 2θ = 24.62°, indicating the absence of well-defined crystalline areas. This characteristic makes the material more suitable for customization in many applications such as drug delivery and tissue engineering. FTIR, SEM, and TGA analysis were performed to gain a better understanding. These findings also emphasize the distinctive qualities and benefits of the oligosaccharides in this domain. Application of chitosan oligosaccharides in the development of efficient drug delivery systems. In the future, it would be more effective, targeted, and safe, with potent therapeutic efficacy for drug delivery.

Computational drug-drug interaction prediction mediated by CYP450 isoforms of Ilaprazole coadministered with clopidogrel.

Ilaprazole due to its pharmacokinetic variability does not affect the clopidogrel efficacy during concomitant use. Methodology: Prediction of DDI for Clopidogrel and PPIs performed using (DDI-Pred) Way2Drug software. The probabilities ΔP, which estimate the potential DDIs resulting from interaction with CYP450 isoenzymes. Results: Positive ΔP-values for CYP2C19 (0.955) indicate that it is involved in the drug interaction of Ilaprazole and Clopidogrel. Discussion: Pantoprazole and Ilaprazole were found to have a low probability of CYP2C19 inhibition Conclusion: Compared with other PPIs, Pantoprazole and Ilaprazole were found to have a low probability of CYP2C19 inhibition; Since Ilaprazole has pharmacokinetic variability, further in vivo and in vitro studies are required on the ilaprazole and clopidogrel combination to assess the effect of drug-drug interaction.

Genetic diversity of cytochrome P450 in patients receiving psychiatric care in Greece: a step towards clinical implementation.

Aim: We herein inferred the genetic diversity of CYP450 isoenzymes to predict the percentage of patients who need dose adjustment in drugs used in psychiatry.Materials & methods: Data of 784 Greek patients receiving psychiatric care who were genotyped for CYP2D6, CYP2C19, CYP1A2, CYP3A5 and CYP2C9 isoenzymes were inferred to gene-drug pairs according to the US FDA, Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group annotations and published literature.Results: Atypical metabolism was found for 36.8% of patients in CYP2D6, 49.2% in CYP2C19, 45% in CYP1A2, 16.7% in CYP3A5 and 41.8% in CYP2C9. Dosage adjustment need was estimated for 10.2% of venlafaxine, 10.0% of paroxetine, 6.4% of sertraline, 30.8% of citalopram, 52.1% of escitalopram, 18.2% of fluvoxamine, 54.1% of tricyclic antidepressants, 16.7% of zuclopenthixol, 10.6% of haloperidoland 13.3% of risperidone treated patients.Conclusion: Clinical psychiatric pharmacogenomic implementation holds promise to improve drug effectiveness and safety.

Ferrocene-bisphosphonates hybrid drug molecules: In vitro antibacterial and antifungal, in silico ADME, drug-likeness, and molecular docking studies

The design of hybrid molecules is a promising drug development strategy to prepare effective antimicrobial drugs that employ the concept of combination therapy. This strategy combines two therapeutic agents covalently to target different cellular pathways for synergistic effects. Ferrocene-bisphosphonate hybrid compounds, 1–8 were evaluated in vitro for their antibacterial and antifungal activities against selected fungal strains, gram-positive, and gram-negative bacteria. Hybrid compounds, 5, 6, and 8 exhibited significant antibacterial activity against all the bacterial strains than the control, fosfomycin with the lowest MIC value of ≤ 3 against Proteus mirabilis and Klebsiella aerogenes. The antifungal activity of hybrids, 2, 4, 5, and 6 against Penicillum Citrinum and Aspergillus ochraceus was high when compared to the control, nystatin. The lowest MIC values were 107 and 214 µM against Penicillum Citrinum and Aspergillus ochraceus for hybrid 5. The molecular docking studies revealed the inhibition of urease enzymes in Klebsiella aerogenes with a high binding energy of −3.973 and −4.645 Kcal/mol, respectively for hybrids 5 and 6. The in silico toxicity revealed the non-toxic effects of the hybrid compounds. The SwissADME parameters of the hybrid molecules further predicted good permeability, water solubility, and oral bioavailability, inability to cross the blood–brain barrier (BBB) and non-inhibition effects on some CYP isoenzymes, suggesting that their biotransformation will not be via the cytochrome isoenzymes. Most of the hybrids, 4–8 were predicted to be P-glycoprotein substrates. The hybrids obeyed Lipinski's rules with one violation, the Ghose rule, and the Egan rule. These findings indicate that the efficacy of hybrid compounds as promising antimicrobials and future studies are needed.

Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice.

Rationale: Liver cirrhosis is known to affect drug pharmacokinetics, but the functional assessment of the underlying pathophysiological alterations in drug metabolism is difficult. Methods: Cirrhosis in mice was induced by repeated treatment with carbon tetrachloride for 12months. A cocktail of six drugs was administered, and parent compounds as well as phase I and II metabolites were quantified in blood, bile, and urine in a time-dependent manner. Pharmacokinetics were modeled in relation to the altered expression of metabolizing enzymes. In discrepancy with computational predictions, a strong increase of glucuronides in blood was observed in cirrhotic mice compared to vehicle controls. Results: The deviation between experimental findings and computational simulations observed by analyzing different hypotheses could be explained by increased sinusoidal export and corresponded to increased expression of export carriers (Abcc3 and Abcc4). Formation of phase I metabolites and clearance of the parent compounds were surprisingly robust in cirrhosis, although the phase I enzymes critical for the metabolism of the administered drugs in healthy mice, Cyp1a2 and Cyp2c29, were downregulated in cirrhotic livers. RNA-sequencing revealed the upregulation of numerous other phase I metabolizing enzymes which may compensate for the lost CYP isoenzymes. Comparison of genome-wide data of cirrhotic mouse and human liver tissue revealed similar features of expression changes, including increased sinusoidal export and reduced uptake carriers. Conclusion: Liver cirrhosis leads to increased blood concentrations of glucuronides because of increased export from hepatocytes into the sinusoidal blood. Although individual metabolic pathways are massively altered in cirrhosis, the overall clearance of the parent compounds was relatively robust due to compensatory mechanisms.

Voriconazole-induced visual abnormality based on drug interaction between voriconazole and esomeprazole: A case report.

We report a case of voriconazole-induced visual abnormality based on drug interaction of voriconazole and esomeprazole, therapeutic drug monitoring, and optimal therapy. An 81-year-old male developed visual abnormality after the blood concentration of voriconazole was up to 6.47 mg/L induced by coadministration with esomeprazole. Voriconazole is a substrate of multiple CYP450 isoenzymes including CYP2C19 (the major route), CYP3A4, and CYP2C9. Esomeprazole, a proton pump inhibitor (PPI), is also converted to inactive metabolites through CYP3A4 and CYP2C19-mediated metabolism, and is also a CYP2C19 inhibitor. The coadministration with esomeprazole inhibited the metabolism of voriconazole via CYP2C19 and promoted the elevation of voriconazole blood concentration beyond the minimum toxic level (5.5mg/L). According to the pharmacist's advice, the adverse effects of visual abnormalities in the patient disappeared after the clinician reduced voriconazole dosage by 50% when other medication schedules remained unchanged. Therefore, therapeutic drug monitoring of voriconazole should be considered in patients receiving PPIs, especially esomeprazole, in order to adjust the dosage in time and achieve optimal therapeutic response and minimal adverse reaction.

Fluorescence-Based High-Throughput Assays for Investigating Cytochrome P450 Enzyme-Mediated Drug-Drug Interactions.

The cytochrome P450 enzymes (CYPs), a group of heme-containing enzymes, catalyze oxidative metabolism of a wide range of drugs and xenobiotics, as well as different endogenous molecules. Strong inhibition of human CYPs is the most common cause of clinically associated pharmacokinetic drug-drug/herb-drug interactions (DDIs/HDIs), which may result in serious adverse drug reactions, even toxicity. Accurate and rapid assessing of the inhibition potentials on CYP activities for therapeutic agents is crucial for the prediction of clinically relevant DDIs/HDIs. Over the past few decades, significant efforts have been invested into developing optical substrates for the human CYPs, generating a variety of powerful tools for high-throughput assays to detect CYP activities in biologic specimens and for screening of CYP inhibitors. This minireview focuses on recent advances in optical substrates developments for human CYPs, as well as their applications in screening CYP inhibitors and DDIs/HDIs studies. The examples for rational design and optimization of highly specific optical substrates for the target CYP enzyme, as well as applications in investigating CYP-mediated DDIs, are illustrated. Finally, the challenges and future perspectives in this field are proposed. Collectively, this review summarizes the reported optical-based biochemical assays for highly efficient CYP activities detection, which strongly facilitated the discovery of CYP inhibitors and the investigations on CYP-mediated DDIs. SIGNIFICANCE STATEMENT: Optical substrates for cytochrome P450 enzymes (CYPs) have emerged as powerful tools for the construction of high-throughput assays for screening of CYP inhibitors. This mini-review covers the advances and challenges in the development of highly specific optical substrates for sensing human CYP isoenzymes, as well as their applications in constructing fluorescence-based high-throughput assays for investigating CYP-mediated drug-drug interactions.

Bortezomib Pharmacogenetic Biomarkers for the Treatment of Multiple Myeloma: Review and Future Perspectives.

Multiple myeloma (MM) is a hematological neoplasm for which different chemotherapy treatments are used with several drugs in combination. One of the most frequently used drugs for the treatment of MM is the proteasome inhibitor bortezomib. Patients treated with bortezomib are at increased risk for thrombocytopenia, neutropenia, gastrointestinal toxicities, peripheral neuropathy, infection, and fatigue. This drug is almost entirely metabolized by cytochrome CYP450 isoenzymes and transported by the efflux pump P-glycoprotein. Genes encoding both enzymes and transporters involved in the bortezomib pharmacokinetic pathway are highly polymorphic. The response to bortezomib and the incidence of adverse drug reactions (ADRs) vary among patients, which could be due to interindividual variations in these possible pharmacogenetic biomarkers. In this review, we compiled all pharmacogenetic information relevant to the treatment of MM with bortezomib. In addition, we discuss possible future perspectives and the analysis of potential pharmacogenetic markers that could influence the incidence of ADR and the toxicity of bortezomib. It would be a milestone in the field of targeted therapy for MM to relate potential biomarkers to the various effects of bortezomib on patients.

Potential profound fluctuation in tacrolimus concentration on consumption of pomegranate rind extract: A Pharmacokinetic Experiment.

Background: Presently, varied case reports demonstrated an increase or decrease in blood concentration of diverse conventional drugs, often co-administered with edible fruits, spices, or vegetables. The overarching aim of this research is to elucidate the fluctuations in tacrolimus (TAC) blood concentration on the consumption of pomegranate rind extract (PRE). Methods: A pharmacokinetic (PK) study was conducted with two groups, vis-a-vis PRE + TAC (3mg/kg) and TAC (3mg/kg) alone groups. An experimental study was conducted in three different manners: Single-dose (S) PRE (200mg/kg), 7-day repetitive (7-R) PRE (200mg/kg) dosing, and multiple (M) PRE doses (100, 200, 400, and 800mg/kg). All the blood samples (approximately 300μl) were drawn at different time intervals, i.e., 30min, 1, 2, 4, 8, and 12h after oral administration of TAC (3mg/kg). The estimation of TAC in rat plasma was done using the hyphenated technique LC-MS/MS where the mass spectrometer used was a triple-stage quadrupole in multiple-reaction monitoring (MRM) mode. Results: The findings depict that in comparison with the TAC (3mg/kg) alone group with the 7-day repetitive (7-R) PRE (200mg/kg) dosing, the Cmax was found to be 9.03 ± 1.21ng/ml; AUC from time zero to infinity (AUC0-∞), 61.91 ± 17.37ngh/ml, while the TAC (3mg/kg) + PRE group exhibited an increase in PK parameters of TAC (Cmax 22.48 ± 3.07ng/ml; AUC0-∞ 153.08 ± 13.24ngh/ml). The authors further investigated in what manner the PRE affects the PK of TAC in animals. For this, docking studies with major phytoconstituents present in the PRE with CYP3A4 isoenzyme were carried out. Ellagitannins (dock score, -11.64) and punicalagin (dock score, -10.68) were again used for molecular simulation studies with TAC. To validate our findings, a CYP3A4 inhibitory in vitro assay was conducted. Conclusion: Based on the integrated in vivo and in silico studies, we concluded that pomegranate rind extract interacts strongly with CYP isoenzyme and is therefore responsible for the altered PK profile of TAC.

Importance of genotyping and phenotyping of CYP450 isoenzymes in the treatment of psychiatric disorders

Importance of genotyping and phenotyping of CYP450 isoenzymes in the treatment of psychiatric disorders

Prospective Prediction of Dapaconazole Clinical Drug-Drug Interactions Using an In Vitro to In Vivo Extrapolation Equation and PBPK Modeling.

This study predicted dapaconazole clinical drug−drug interactions (DDIs) over the main Cytochrome P450 (CYP) isoenzymes using static (in vitro to in vivo extrapolation equation, IVIVE) and dynamic (PBPK model) approaches. The in vitro inhibition of main CYP450 isoenzymes by dapaconazole in a human liver microsome incubation medium was evaluated. A dapaconazole PBPK model (Simcyp version 20) in dogs was developed and qualified using observed data and was scaled up for humans. Static and dynamic models to predict DDIs following current FDA guidelines were applied. The in vitro dapaconazole inhibition was observed for all isoforms investigated, including CYP1A2 (IC50 of 3.68 µM), CYP2A6 (20.7 µM), 2C8 (104.1 µM), 2C9 (0.22 µM), 2C19 (0.05 µM), 2D6 (0.87 µM), and 3A4 (0.008−0.03 µM). The dynamic (PBPK) and static DDI mechanistic model-based analyses suggest that dapaconazole is a weak inhibitor (AUCR > 1.25 and <2) of CYP1A2 and CYP2C9, a moderate inhibitor (AUCR > 2 and <5) of CYP2C8 and CYP2D6, and a strong inhibitor (AUCR ≥ 5) of CYP2C19 and CYP3A, considering a clinical scenario. The results presented may be a useful guide for future in vivo and clinical dapaconazole studies.

754. Olorofim for treatment of invasive fungal infections (IFI) due to moulds in patients with limited or no treatment options: Interim results from a Phase 2b open-label study (NCT03583164, Study 32)

Abstract Background Olorofim, the first orotomide antifungal, selectively inhibits fungal dihydroorotate dehydrogenase (DHODH), a key enzyme in fungal pyrimidine biosynthesis. Olorofim is active against Aspergillus (including azole-resistant and cryptic species), resistant moulds (e.g., Lomentospora prolificans, Scopulariopsis) and dimorphic fungi (e.g., Coccidioides). The drug is given orally and cleared by multiple CYP450 isoenzymes. Serial images via bronchoscope of Scopulariopsis infection at the anastamosis in a lung transplant patient, pre- and post-olorofim therapy. After lung transplant, airway obstruction at the anastomosis due to Scopulariopsis was unresponsive to available antifungal agents. The airway was clear by day 10 on olorofim monotherapy. Infection was cured with 84 days of olorofim. Methods Patients with limited or no treatment options for proven invasive mycoses or probable pulmonary invasive aspergillosis (IA, as per 2020 EORTC-MSGERC criteria) received olorofim (loading dose of 150mg BID on day 1, followed by 90mg BID) for up to 90 days, with extended therapy beyond day 90 allowed. The primary endpoint was DRC-adjudicated overall response rate by pathogen at day 42 using the EORTC-MSG response criteria. Results At database lock for the first 100 cases, infecting fungi were Aspergillus species (53, including 13 azole-resistant species), L. prolificans (17), Scedosporium (11), Coccidioides (11), and other fungi (8). Success (complete or partial response) was 44% at day 42 and 39% at day 84. When stable disease was counted as success, the success rate was 69% and 59% respectively. Response was seen in patients with highly active, uncontrolled infection (Figure). Overall all-cause mortality was 14% and 19% at day 42 and 84 respectively (IA: 23% and 30%; non-IA infections 4% and 6% respectively). Safety: Olorofim was well tolerated over the 84d median dosing duration (max 722 days). Altered hepatic biochemistry possibly due to olorofim was seen in 8% of study subjects and managed by dose reduction/pause and led to discontinuation in 2%. Mild, self-limiting GI intolerance was noted in 2%. Conclusion Olorofim is an oral, mechanistically novel anti-mould agent with activity against a range of mould infections which are difficult to treat. Olorofim has a positive risk-benefit profile in a well-defined population of patients with infections due to moulds including species considered resistant to all approved antifungals. Disclosures Johan A. Maertens, MD PhD, F2G Ltd: Advisor/Consultant|Gilead Sciences Ltd: Advisor/Consultant|Mundipharma: Advisor/Consultant|Pfizer Inc: Advisor/Consultant George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Andrej Spec, MD, MSCI, Astellas: Grant/Research Support Sarah P. Hammond, MD, F2G: Advisor/Consultant|F2G: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|pfizer: Advisor/Consultant|Scynexis: Grant/Research Support Bart Rijnders, MD, PhD, F2G: Advisor/Consultant P. Lewis White, PhD, Associates of Cape Cod: Honoraria|F2G: Advisor/Consultant|Gilead: Grant/Research Support|IMMY: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria Oliver A. Cornely, Prof. Dr., Abbott: Honoraria|Abbvie: Advisor/Consultant|Actelion: Board Member|Al-Jazeera Pharmaceuticals: Honoraria|Allecra Therapeutics: Board Member|Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Honoraria|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|Biocon: Advisor/Consultant|Biosys: Advisor/Consultant|BMBF: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Board Member|Cidara: Expert Testimony|Cidara: Grant/Research Support|CoRe Consulting: Stocks/Bonds|Da Volterra: Advisor/Consultant|DLR: Grant/Research Support|DZIF: Grant/Research Support|Entasis: Board Member|EU Directorate-General for Resarch and Innovation: Grant/Research Support|F2G: Grant/Research Support|German Patent and Trade Mark Office: German patent (DE 10 2021 113 007.7)|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Grupo Biotoscana/United Medical/Knight: Honoraria|Hikma: Honoraria|IQVIA: Board Member|Janssen: Board Member|Matinas: Advisor/Consultant|Matinas: Grant/Research Support|MedPace: Advisor/Consultant|MedPace: Grant/Research Support|MedScape: Honoraria|MedUpdate: Honoraria|Menarini: Advisor/Consultant|Merck/MSD: Grant/Research Support|Merck/MSD: Honoraria|Molecular Partners: Advisor/Consultant|MSG-ERC: Advisor/Consultant|Mundipharma: Grant/Research Support|Mylan: Honoraria|Noxxon: Advisor/Consultant|Octapharma: Advisor/Consultant|Octapharma: Grant/Research Support|Paratek: Board Member|Pardes: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Projektträger Jülich: Grant/Research Support|PSI: Advisor/Consultant|PSI: Board Member|Pulmocide: Board Member|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support|Seres: Advisor/Consultant|Shionogi: Board Member|Wiley (Blackwell): Editor-in-Chief, Mycoses Lesley Fitton, BSc, F2G Ltd: Employee|F2G Ltd: Stocks/Bonds Aaron Dane, MSc, Amplyx: Advisor/Consultant|AN2 therapeutics: Advisor/Consultant|Artizan: Advisor/Consultant|Cidara: Advisor/Consultant|ContraFect: Advisor/Consultant|Correvio: Advisor/Consultant|Davolterra: Advisor/Consultant|Destiny Pharma: Advisor/Consultant|Entasis: Advisor/Consultant|F2G Limited: Advisor/Consultant|GSK: Advisor/Consultant|Humanigen: Advisor/Consultant|Kymab: Advisor/Consultant|Modis: Advisor/Consultant|Orca: Advisor/Consultant|Pfizer: Advisor/Consultant|Phico: Advisor/Consultant|Pled Pharma: Advisor/Consultant|Rare Thyroid: Advisor/Consultant|Roche: Advisor/Consultant|Scynexis: Advisor/Consultant|Sinovent: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant|Transcrip: Advisor/Consultant|Venatorx: Advisor/Consultant John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant Sharon C. Chen, PhD MBBS, F2G PTy Ltd: Grant/Research Support|MSD Australia: Grant/Research Support.

Variations in the Frequencies of Polymorphisms in the CYP450s Genes in Eight Major Ethnicities of Iran: A Review of the Human Data.

Genetic polymorphisms in cytochrome P450 genes can cause variation in metabolism. Thus, single nucleotide variants significantly impact drug pharmacokinetics, toxicity factors, and efficacy and safety of medicines. The distribution of CYP450 alleles varies drastically across ethnicities, with significant implications for personalized medicine and the healthcare system. We combined whole-genome and exome sequencing data to provide a review of CYP450 allele polymorphisms with clinical importance. Data were collected from 800 unrelated Iranians (100 subjects from 8 major ethnicities of Iran), more than 32,000 unrelated Europeans (other than Caucasian), and four Middle Eastern countries. We analyzed the frequencies and similarities of 17 CYP450 frequent alleles related to nine important CYP450 isoenzymes and homozygous and heterozygous genotypes based on these alleles in eight major Iranian ethnics by integrating these data with population-specific linkage information and compared these datasets with mentioned populations.

PSAT050 An Unusual Case of Adrenal Insufficiency After Using Budesonide for Treatment of Microscopic Colitis

Abstract Introduction Long term use of systemic glucocorticoids are a common cause of secondary adrenal insufficiency from 1.4-27.5% of cases. On the other hand, Budesonide, a non-halogenated steroid that is widely used for its low systemic absorption is rarely reported to cause secondary adrenal insufficiency. Case A 39-year-old female with significant medical history of anxiety, bipolar disorder, hypothyroidism, type 2 DM and lymphocytic colitis was admitted to the hospital with acute mental status change and lethargy. She reported a 3-week history of diffuse abdominal pain and diarrhea. She endorsed weight loss but denied any fever, vomiting, recent infection or any significant history of hepatitis. In ER, her vitals were notable for a BP of 105/68 mm Hg, Pulse 76 beats/min, temperature 97.5F, pulse oximetry 100% with 2 L nasal canula. On examination she appeared frail, alert but mildly confused. Admission labs showed sodium 143, potassium 4.3, bicarbonate 15, creatinine 1.2, GFR 57, blood glucose 67, Hemoglobin 6.3 and WBC 4.3, UA negative. During the ER course she became hypotensive with SBP in 80s. She was fluid resuscitated with a total of 4 L of normal saline and was eventually started on vasopressor support due to profound hypotension unresponsive to fluids. One unit of PRBC was transfused and she was transferred to MICU for further monitoring. Baseline cortisol level was drawn, and she was started on dexamethasone for presumed adrenal insufficiency, while awaiting the result of her labs. Her cortisol was subsequently confirmed to be 5.5mcg/dl. She was maintained on stress dose steroids and experienced dramatic improvements in her clinical status and BP. A review of her medical history revealed that she was diagnosed with microscopic colitis 5 months prior to the current admission and had been placed on budesonide 9mg/day, tapered slowly to the current dose of 3mg/day. She reported compliance with her budesonide up to the date of the admission. Discussion Iatrogenic adrenal insufficiency from Budesonide is rarely reported in the literature. Budesonide is a common choice for IBD, especially Crohn's disease and microscopic colitis. It has a high first pass metabolism (80-90%), thus limiting its systemic bioavailability to as low as 9-21%. Despite that, a few cases of chronic oral Budesonide use resulting in AI have been reported. As it is metabolized in the liver via CYP450 isoenzymes, concurrent use of CYP450 inhibitors or hepatic cirrhosis can also potentially interfere with its metabolism and increase its systemic bioavailability. According to literature there have been a few descriptions of patients developing AI without prior liver disease, similar to our patient. Caution should therefore be exercised in prescribing budesonide and physicians should have a high index of suspicion when patients on budesonide present with symptoms suggestive of adrenal insufficiency. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Interaction study of salvianolic acids for injection on pharmacokinetics of clopidogrel in rats using LC-MS/MS.

Salvianolic acids for injection (SAI) is developed from traditional Chinese medicine and approved for the treatment of cardiovascular and cerebrovascular diseases. Clopidogrel is an inhibitor of platelet aggregation, which is often prescribed for patients in combination with SAI. This present study aimed to assess the effects of SAI on the pharmacogenomics, pharmacokinetics, and pharmacodynamics of clopidogrel, thereby ensuring the safety and efficacy of coadministration. In vitro cytochrome P450 isoenzyme assays were performed in human liver microsomes using LC-MS/MS method to assess the metabolites of CYPs substrates. The effects of SAI on the pharmacokinetic and pharmacodynamic behaviors of clopidogrel were investigated in rats. The main pharmacokinetic parameters were analyzed using LC-MS/MS. Prothrombin time, activated partial thromboplastin time, bleeding time, and inhibition of platelet aggregation were measured to evaluate the effects of pharmacodynamics. Our study revealed that the clinical dose of SAI has no significant inhibitory effect on clopidogrel-related liver microsome metabolic CYP450 isoenzymes. Moreover, SAI did not affect the pharmacokinetics of clopidogrel when rats were administered both single and multiple doses. In pharmacodynamic study, SAI has no effect on platelet aggregation rate, prothrombin time, and activated partial thromboplastin time of clopidogrel but could significantly prevent the risk of bleeding caused by clopidogrel.

SKLB-14b, a novel oral microtubule-destabilizing agent based on hydroxamic acid with potent anti-tumor and anti-multidrug resistance activities

A hydroxamic acid based microtubule-destabilizing agent (MDA) SKLB-14b was discovered in this study, which was derived from shortening the linker length of the HDAC6 and microtubule dual-target inhibitor SKLB-23bb. SKLB-14b exhibited low nanomolar IC50 values on a wide spectrum of human cancer cell lines including both sensitive and multidrug-resistant cell lines. Surprisingly, its anti-proliferative activity relied on the presence of the hydroxamic acid group but lost inhibitory activity against HDACs. SKLB-14b bound to the colchicine site of tubulin and could inhibit tubulin polymerization. It exhibited good metabolic stability in liver microsomes, no inhibitory effect on CYP450 isoenzymes and high oral bioavailability. In vivo experiments revealed that SKLB-14b was potent in both sensitive (A2780S, HCT116) and resistant (A2780/T) xenograft mice models. Furthermore, in the patient-derived tumor xenograft (PDX) models of osimertinib resistant non-small cell lung cancer (NSCLC), 50 mg/kg of SKLB-14b administered every twodays inhibited tumor growth by 70.6% without obvious toxicity, better than the 59.7% inhibition rate of paclitaxel. Mechanistically, we found that SKLB-14b exerted anti-tumor and anti-multidrug resistance effects in vitro and in vivo through cell cycle arrest and pro-apoptotic activities, as well as vascular disrupting activities. Therefore, we discovered that SKLB-14b, as a novel MDA based on hydroxamic acid, could serve as a potential drug candidate for cancer therapy which deserves further investigation.

New Developments in Pediatric Antifungal Pharmacology.

New Developments in Pediatric Antifungal Pharmacology.

Efek Polimorfisme Gen Enzim Pemetabolisme Obat terhadap Kadar Rivaroxaban: Sebuah Kajian Naratif

Rivaroxaban is an anticoagulant agent that often experience biotransformation in the liver through CYP3A4/5 (18%); CYP2J2 (14%) and CYP independent hydrolytic cleavage (14%). Several studies revealed that Polymorphism in drug-metabolizing enzyme genes can affect the rivaroxaban levels in the body. Therefore, this study aims to review the effect of gene variations of metabolizing enzymes on rivaroxaban concentration in patient’s body. A search using keyword rivaroxaban, polymorphism, CYP3A4, CYP3A5 and CYP2J2 was carried out in Google Scholar. Several studies showed that polymorphisms of metabolizing genes do not have a significant effect on rivaroxaban concentration. There is also a need for comprehensive studies involving all single nucleotide polymorphisms (SNPs) that play a role in the drug’s pharmacokinetics. This is because rivaroxaban is metabolized by several CYP isoenzymes and excreted by different transporters. This still opens the opportunity for further studies on its pharmacogenomic.