CYP450 Pathway Research Articles

Prevalence of recreational and medical cannabis products in Veterans and their interactions with cancer directed pharmacological treatment.

3089 Background: There is proliferation of literature about the medical uses of cannabis products in patients with malignancies. However, research is lacking as to how cannabis use is affecting the efficacy and toxicity of anti-neoplastic regimens It is known that cannabis is metabolized by the cytochrome p450 pathway, the same as many anti-neoplastic agents and thus there are concerns for potential interactions. Methods: We report an observational study to identify cannabis users in veterans receiving anti-neoplastic therapy in the Memphis VA health system, and to then analyzed for potential interactions between cannabis product and the antineoplastic agent/s they were receiving. Data was collected via voluntary surveys. We then reviewed their charts, recorded the anti- neoplastic medications they were receiving, and evaluated for potential interactions with cannabis, based on a literature review of potential interactions. Results: In this study, 132 veterans agreed to participate. 50 of them acknowledged recent use of cannabis products within the last 90 days. Thus, the prevalence of cannabis use amongst those who participated is 37.87%. Demographically, 10% of the cannabis users were female, and 90% were male, with the majority aged 60-65 (range 46-85). Predominantly, patients inhaled cannabis once daily (38%) as opposed to using a different formulation. The patients who admitted cannabis use were primarily on chemotherapy (42%), while 38% were on immunotherapy, 24% were on targeted therapy and 20% were on endocrine therapy. Some were on multiple drugs. Based on this data and a literature search for interactions, we found that a significant number of the patients in our Veteran’s oncology clinic have a potential increase in toxicity or decreased efficacy from their ant-neoplastic therapy due to CYP interactions with cannabis use. Conclusions: In this exploratory study, we discovered a notable prevalence of patients concurrently using cannabis products while on anti-neoplastic treatment. Given that many anti-neoplastic agents undergo metabolism via the CYP450 pathway, our data suggest that a moderate number of patients in our clinic risk less than optimal outcomes due to concurrent cannabis and anti-neoplastic therapy. To delve deeper, we intend to conduct a follow-up study, focusing on specific adverse effects, hospitalizations, and the subsequent need for 2nd and 3rd line treatments in patients using cannabis. A much larger multi-institutional study should be considered to provide statistically relevant data on true outcomes. [Table: see text]

Sex Difference in Reliance on CYP450 Contribution to Functional Sympatholysis in Healthy, Young Adults

Sex differences in functional sympatholysis have provided conflicting results, in both animal and human models. Further, investigations into underlying functional sympatholysis mechanisms between the sexes are largely unexplored. PURPOSE: To investigate if functional sympatholysis differs between biological sexes and to explore whether CYP450 inhibition alters functional sympatholysis between sexes. METHODS: Healthy males (n=12, 21±2 years) and females (n=12, 23±3 years, tested in early follicular phase) participated in three study visits (2 experimental). 120min prior to experimental testing, a placebo (PLA, 250 mg microcrystalline cellulose) or CYP450 2C9 inhibitor (150 mg fluconazole, FLZ) were ingested in a randomized, counter-balanced design. Beat-to-beat forearm muscle blood flow (FBF, doppler ultrasound) and mean arterial pressure (MAP, finger photoplethysmography), were measured continuously to calculate vascular conductance (FVC= FBF/MAPx100mmHg). Measurements were taken during 5 minutes of rest and lower body negative pressure (LBNP; -20mmHg) in resting conditions for 2 minutes. Following 10 minutes of rest, steady state rhythmic handgrip exercise (EX; 20% maximum voluntary contraction; 2 sec contraction, 1 sec relaxation duty cycles) was applied for 7 minutes with LBNP added for the last 2 minutes (Ex+LBNP). The magnitude of functional sympatholysis (%) was calculated as (functional sympatholysis (%) = Δ%FVC Ex+LBNP - Δ%FVC LBNP). Impairment to functional sympatholysis in response to CYP450 inhibition was calculated as the difference in functional sympatholysis (%) between the PLA and the FLZ condition. Results: Data are means ± SD. The magnitude of functional sympatholysis was not different between sexes in either PLA (Males: 33.91±20.91 % vs. Females: 38.43±21.71 %, P: 0.61 d: 0.21) nor FLZ (Males: 30.83±29.95 % vs. Females: 18.40±26.56 %, P: 0.23 r: 0.026). The impairment to functional sympatholysis in response to CYP450 inhibition was not different between sexes (Males: -3.07±20.02% vs. Women: -20.02±39.80%, P: 0.23, d: 0.5) with a moderate to large effect size. However, a two one-sided test (TOST) was used to test whether sexes had equivalent in responses to CYP450 inhibition and revealed non-significance ( t(18.86) = 0.574, p = 0.714) and thus non-equivalence. CONCLUSION: Our findings support previous investigation confirming no sex differences in functional sympatholysis in humans. However, our results indicate that sexes did not show equivalent responses to CYP450 inhibition despite non-significance. These findings advocate that females may be more reliant of CYP450 pathways for functional sympatholysis then men and future exploration is warranted. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Therapeutic Drug Monitoring and Pharmacogenetic Testing as Guides to Psychotropic Drug Dose Adjustment: An Observational Study.

To avoid the failures in therapy with psychotropic drugs, treatments can be personalized by applying the results of therapeutic drug monitoring and pharmacogenetic testing. The objective of the present single-center observational study was to describe the changes in psychotropic drug management prompted by therapeutic drug monitoring and pharmacogenetic testing, and to compare the effective drug concentration based on metabolic status with the dose predicted using an in silico decision tool for drug-drug interactions. The study was conducted in psychiatry wards at Lille University Hospital (Lille, France) between 2016 and 2020. Patients with data for at least one therapeutic drug monitoring session or pharmacogenetic test were included. Blood tests were performed for 490 inpatients (mainly indicated by treatment monitoring or failure) and mainly concerned clozapine (21.4%) and quetiapine (13.7%). Of the 617 initial therapeutic drug monitoring tests, 245 (40%) complied with good sampling practice. Of the patients, 51% had a drug concentration within the therapeutic range. Regardless of the drug concentration, the drug management did not change in 83% of cases. Thirty patients underwent pharmacogenetic testing (twenty-seven had also undergone therapeutic drug monitoring) for treatment failure; the plasma drug concentration was outside the reference range in 93% of cases. The patient's metabolic status explained the treatment failure in 12 cases (40%), and prompted a switch to a drug metabolized by another CYP450 pathway in 5 cases (42%). Of the six tests that could be analyzed with the in silico decision tool, all of the drug concentrations after adjustment were included in the range estimated by the tool. Knowledge of a patient's drug concentration and metabolic status (for CYD2D6 and CYP2C19) can help clinicians to optimize psychotropic drug adjustment. Drug management can be optimized with good sampling practice, support from a multidisciplinary team (a physician, a geneticist, and clinical pharmacist), and decision support tools.

637-P: Sex-Specific Associations between Fatty Acid–Derived Oxylipins and Executive Function in T2DM

T2DM increases the risk of cognitive decline, especially in women. Sex-specific associations between lipids and cognition have been reported, though underlying mechanisms remain unclear. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway have been linked to both T2DM and cognitive dysfunction. CYP450s convert long-chain polyunsaturated fatty acids into epoxides which are anti-inflammatory and help resolve inflammation, however sEH metabolizes these into inactive or cytotoxic diols, limiting their benefits. We hypothesized that oxylipin epoxides and diols of arachidonic acid (AA) and docosahexaenoic acid (DHA) would be associated with cognition in people with T2DM, particularly in women. Women and men with T2DM were recruited as part of the study. Twenty-two fasting serum free oxylipins were quantified by ultra-high performance liquid chromatography tandem mass spectrometry. Executive function was assessed using a composite z-score from the following tests: Stroop Colour-Word Interference Victoria Version, FAS Verbal Fluency, Digit Symbol Substitution, and Trails Making Test Part B. All analyses controlled for age, sex, BMI, HbA1c and years of education. Among 72 individuals with T2DM (mean age 61.8±9.2, mean HbA1c 7.4±0.1%, 53% women), demographic characteristics, oxylipin concentrations and cognitive performance did not differ between women and men. Some CYP450-derived epoxides of DHA and AA were associated with lower executive function scores in women, but with higher scores in men. Epoxide × sex interactions were found for 3 of 4 DHA epoxides (16(17) [F=20.2, p<0.001]; 13(14) [F=8.5, p=0.005]; and 10(11) [F=7.4, p=0.009]), and for the 14(15) AA epoxide [F=3.9, p<0.05]). Circulating concentrations of the corresponding diols were not associated with executive function. These associations between epoxides and executive function suggest a sex difference in the relevance of the CYP450 pathway to cognitive performance in T2DM. Disclosure S.Ryoo: None. B.R.Shah: None. J.Gilbert: Speaker's Bureau; Abbott, AstraZeneca, Amgen Canada, Bayer Inc., Boehringer Ingelheim (Canada) Ltd., Sanofi, Dexcom, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Novo Nordisk Canada Inc. A.Assal: None. I.Halperin: Advisory Panel; Sanofi, Speaker's Bureau; 3Boehringer Ingelheim Canada Ltd./Ltée, Abbott Diabetes, Dexcom, Inc., Novo Nordisk. A.Taha: None. W.Swardfager: None. N.Z.Anita: None. C.Major-orfao: None. W.Lin: None. S.Noor: None. F.Kwan: None. K.L.Lanctôt: Consultant; Exciva, GW Pharmaceuticals, ICG Farma, Merck Sharp & Dohme Corp., Novo Nordisk, Sumitomo Pharma Co. Ltd., Other Relationship; BioXcel, Cerevel Therapeutics, H Lundbeck A/S. N.Herrmann: None. P.Oh: Advisory Panel; Novartis Canada. Funding Canadian Institutes of Health Research; Banting & Best Diabetes Centre; National Institute of Diabetes and Digestive and Kidney Diseases

Dynamic Transcriptomic Profiling During Liver Development in Schizothorax Prenanti.

Liver is an important organ for glucose and lipid metabolism, immunity, and detoxification in fish. However, the gene regulatory network of postnatal liver development still remains unknown in teleost fish. In this study, we performed transcriptome analysis on the liver of S. prenanti at three stages. A total of 1692 differentially expressed genes (DGEs) were identified across three liver developmental stages. The oil red O staining and PAS staining revealed that the lipid content of liver was increased and the glycogen content of liver was decreased during liver development. The fatty acids biosynthesis related genes were upregulated in adult and young stages compared with juvenile stage, while lipid degradation related genes were downregulated. The genes related to glycolysis, gluconeogenesis and glycogenolysis were upregulated in juvenile or young stages compared with adult stage. Further pathway analysis indicated that the CYP450 pathway, cell cycle and amino acid metabolic pathway were induced in the process of liver maturation. Our study presents the gene expression pattern in different liver development stages of S. prenanti and may guide future studies on metabolism of S. prenanti liver.

Hepatoprotective Effect of Oplopanax elatus Nakai Adventitious Roots Extract by Regulating CYP450 and PPAR Signaling Pathway.

O. elatus Nakai is a traditional medicine that has been confirmed to exert effective antioxidant and anti-inflammatory functions, and is used for the treatment of different disorders. However, its potential beneficial effects on drug induced hepatotoxicity and relevant molecular mechanisms remain unclear. This study investigated the protective effect and further elucidated the mechanisms of action of O. elatus on liver protection. O. elatus chlorogenic acids-enriched fraction (OEB), which included chlorogenic acid and isochlorogenic acid A, were identified by HPLC-MS/MS. OEB was administrated orally daily for seven consecutive days, followed by a single intraperitoneal injection of an overdose of APAP after the final OEB administration. The effects of OEB on immune cells in mice liver were analyzed using flow cytometry. APAP metabolite content in serum was detected using HPLC-MS/MS in order to investigate whether OEB affects CYP450 activities. The intestinal content samples were processed for 16 s microbiota sequencing. Results demonstrated that OEB decreased alanine aminotransferase, aspartate aminotransferase contents, affected the metabolism of APAP, and decreased the concentrates of APAP, APAP-CYS and APAP-NAC by inhibiting CYP2E1 and CYP3A11 activity. Furthermore, OEB pretreatment regulated lipid metabolism by affecting the peroxisome proliferator-activated receptors (PPAR) signaling pathway in mice and also increased the abundance of Akkermansia and Parabacteroides. This study indicated that OEB is a potential drug candidate for treating hepatotoxicity because of its ability to affect drug metabolism and regulate lipid metabolism.

Deregulation of Arachidonic Acid Metabolism CYP450 Pathway is Associated with Microvascular Invasion in Hepatocellular Carcinoma

Deregulation of Arachidonic Acid Metabolism CYP450 Pathway is Associated with Microvascular Invasion in Hepatocellular Carcinoma

Effects of Real-Ambient PM2.5 Exposure on Lung Damage Modulated by Nrf2-/.

Previous studies have shown that long-term exposure to fine particulate matter (PM2.5) increases the morbidity and mortality of pulmonary diseases such as asthma, chronic obstructive pulmonary disease and pulmonary emphysema. Oxidative stress and inflammation play key roles in pulmonary damage caused by PM2.5. Nuclear factor erythroid 2-related factor 2 (Nrf2) could regulate the expression of antioxidant and anti-inflammatory genes and is pivotal for protection against PM2.5-induced oxidative stress. In this study, a real-ambient exposure system was constructed with the outdoor ambient air in north China. Wild-type (WT) and Nrf2−/− (KO) mice were exposed to the real-ambient system for six weeks. After PM2.5 exposure, our data showed that the levels of inflammatory factors and malondialdehyde were significantly increased in WT and KO mice. Moreover, the lung function and pathological phenotype of the WT mice were altered but there was no obvious change in the Nrf2−/− mice. To further explore the potential molecular mechanisms, we performed RNA-sequencing. The RNA-sequence analysis results showed that the CYP450 pathway in the first ten pathways of KEGG was related to the metabolism of PM2.5. In WT and KO mice, the expression of CYP2E1 in the CYP450 pathway showed opposite trends after PM2.5 exposure. The data showed that the expression of the CYP2E1 gene in WT-PM mice increased while it decreased in KO-PM; the expression of the CYP2E1 protein showed a similar trend. CYP2E1 is primarily distributed in the endoplasmic reticulum (ER) where it could metabolize various exogenous substances attached to PM2.5 and produce highly toxic oxidation products closely related to ER stress. Consistently, the expression level of GRP94, a biomarker of ER stress, was increased in WT mice and reduced in KO mice under PM2.5 exposure. Persistent ER stress is a mechanism that causes lung damage under PM2.5 exposure. Nrf2 facilitates lung injury during PM2.5 exposure and CYP2E1 metabolism is involved in this process.

Different Influences of trans Fatty Acids on the Phospholipase A2 and Arachidonic Acid Metabolic Pathway in Hepatocytes.

This study investigated the effects of 9t18:1 (representing I-TFAs), 9t16:1, and 11t18:1 (representing R-TFAs) and their mixtures on the normal human hepatocyte LO2 cell function, the possible mechanism of lipid metabolism by lipidomics, and the relationship between phospholipase A2 (PLA2) and the arachidonic acid (AA) metabolic pathway. Here, we found that the damaging effect of 9t18:1 on the LO2 cell function was significantly greater than those of 11t18:1 and 9t16:1 (p < 0.05), and the damaging effects of CHB and HSO were significantly greater than those of HHB and CM (p < 0.05). The lipidomic results showed that TFAs and TFA mixtures caused a significant change in the lipid profiles of LO2 cells, in which the TAG, PL, and OL contents increased significantly. Moreover, 9t18:1 regulated only the protein expression of cPLA2 but did not participate in the AA metabolic pathway, while 11t18:1 and 9t16:1 participated in the COX-2 and CYP450 pathways, respectively.

Ibuprofen alters epoxide hydrolase activity and epoxy-oxylipin metabolites associated with different metabolic pathways in murine livers

Over the last decade oxylipins have become more recognized for their involvement in several diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are known to inhibit cyclooxygenase (COX) enzymes, but how NSAIDs affect oxylipins, in addition to COX products, in animal tissues is not well understood. Oxylipins in livers from male and female mice treated with 100 mg/kg/day of ibuprofen for 7 days were investigated. The results showed that ibuprofen treated male livers contained 7 times more altered oxylipins than ibuprofen treated female livers. In male and female livers some prostaglandins were altered, while diols, hydroxy fatty acids and epoxides were significantly altered in male livers. Some soluble epoxide hydrolase (sEH) products, such as 9,10-DiHODE were found to be decreased, while sEH substrates (such as 9(10)-EpODE and 5(6)-EpETrE) were found to be increased in male livers treated with ibuprofen, but not in ibuprofen treated female livers. The enzymatic activities of sEH and microsomal epoxide hydrolase (mEH) were elevated by ibuprofen in both males and females. Analyzing the influence of sex on the effect of ibuprofen on oxylipins and COX products showed that approximately 27% of oxylipins detected were influenced by sex. The results reveal that ibuprofen disturbs not only the COX pathway, but also the CYP450 and lipoxygenase pathways in male mice, suggesting that ibuprofen is likely to generate sex related differences in biologically active oxylipins. Increased sEH activity after ibuprofen treatment is likely to be one of the mechanisms by which the liver reduces the higher levels of EpODEs and EpETrEs.

Regorafenib therapy for hepatocellular carcinoma in a HIV‐1‐infected patient: A case report

Regorafenib therapy for hepatocellular carcinoma in a HIV‐1‐infected patient: A case report

Vascular Lipidomic Profiling of Potential Endogenous Fatty Acid PPAR Ligands Reveals the Coronary Artery as Major Producer of CYP450-Derived Epoxy Fatty Acids.

A number of oxylipins have been described as endogenous PPAR ligands. The very short biological half-lives of oxylipins suggest roles as autocrine or paracrine signaling molecules. While coronary arterial atherosclerosis is the root of myocardial infarction, aortic atherosclerotic plaque formation is a common readout of in vivo atherosclerosis studies in mice. Improved understanding of the compartmentalized sources of oxylipin PPAR ligands will increase our knowledge of the roles of PPAR signaling in diverse vascular tissues. Here, we performed a targeted lipidomic analysis of ex vivo-generated oxylipins from porcine aorta, coronary artery, pulmonary artery and perivascular adipose. Cyclooxygenase (COX)-derived prostanoids were the most abundant detectable oxylipin from all tissues. By contrast, the coronary artery produced significantly higher levels of oxylipins from CYP450 pathways than other tissues. The TLR4 ligand LPS induced prostanoid formation in all vascular tissue tested. The 11-HETE, 15-HETE, and 9-HODE were also induced by LPS from the aorta and pulmonary artery but not coronary artery. Epoxy fatty acid (EpFA) formation was largely unaffected by LPS. The pig CYP2J homologue CYP2J34 was expressed in porcine vascular tissue and primary coronary artery smooth muscle cells (pCASMCs) in culture. Treatment of pCASMCs with LPS induced a robust profile of pro-inflammatory target genes: TNFα, ICAM-1, VCAM-1, MCP-1 and CD40L. The soluble epoxide hydrolase inhibitor TPPU, which prevents the breakdown of endogenous CYP-derived EpFAs, significantly suppressed LPS-induced inflammatory target genes. In conclusion, PPAR-activating oxylipins are produced and regulated in a vascular site-specific manner. The CYP450 pathway is highly active in the coronary artery and capable of providing anti-inflammatory oxylipins that prevent processes of inflammatory vascular disease progression.

Broad Lipidomic and Transcriptional Changes of Prophylactic PEA Administration in Adult Mice.

Beside diverse therapeutic properties of palmitoylethanolamide (PEA) including: neuroprotection, inflammation and pain alleviation, prophylactic effects have also been reported in animal models of infections, inflammation, and neurological diseases. The availability of PEA as (ultra)micronized nutraceutical formulations with reportedly no side effects, renders it accordingly an appealing candidate in human preventive care, such as in population at high risk of disease development or for healthy aging. PEA’s mode of action is multi-facetted. Consensus exists that PEA’s effects are primarily modulated by the peroxisome proliferator-activated receptor alpha (PPARα) and that PEA-activated PPARα has a pleiotropic effect on lipid metabolism, inflammation gene networks, and host defense mechanisms. Yet, an exhaustive view of how the prophylactic PEA administration changes the lipid signaling in brain and periphery, thereby eliciting a beneficial response to various negative stimuli remains still elusive. We therefore, undertook a broad lipidomic and transcriptomic study in brain and spleen of adult mice to unravel the positive molecular phenotype rendered by prophylactic PEA. We applied a tissue lipidomic and transcriptomic approach based on simultaneous extraction and subsequent targeted liquid chromatography-multiple reaction monitoring (LC-MRM) and mRNA analysis by qPCR, respectively. We targeted lipids of COX-, LOX- and CYP450 pathways, respectively, membrane phospholipids, lipid products of cPLA2, and free fatty acids, along with various genes involved in their biosynthesis and function. Additionally, plasma lipidomics was applied to reveal circulatory consequences and/or reflection of PEA’s action. We found broad, distinct, and several previously unknown tissue transcriptional regulations of inflammatory pathways. In hippocampus also a PEA-induced transcriptional regulation of neuronal activity and excitability was evidenced. A massive downregulation of membrane lipid levels in the splenic tissue of the immune system with a consequent shift towards pro-resolving lipid environment was also detected. Plasma lipid pattern reflected to a large extent the hippocampal and splenic lipidome changes, highlighting the value of plasma lipidomics to monitor effects of nutraceutical PEA administration. Altogether, these findings contribute new insights into PEA’s molecular mechanism and helps answering the questions, how PEA prepares the body for insults and what are the “good lipids” that underlie this action.

Dietary arachidonic acid decreases the expression of transcripts related to adipocyte development and chronic inflammation in the adipose tissue of juvenile grass carp, Ctenopharyngodon idella

Overdevelopment of adipose tissue in cultured fish is one of the biggest issues plaguing current aquaculture industry, leading to unhealthy status of fishes and production losses. Diet supplemented with 0.30% arachidonic acid (ARA) has been found to reduce adipogenesis and inflammation in grass carp, but the potential mechanism is not comprehensively understood. To fully reveal the effects of dietary ARA on the mRNA profiles of adipose tissue, transcriptome techniques were applied in this study. A 10-weeks feeding experiment was performed using two isonitrogenous and isoenergetic purified diets, namely ARA-free (control) and 0.30% ARA (ARA group). Results showed increased ARA content and decreased intraperitoneal fat index and adipocyte size in the adipose tissue of fish fed ARA (P < 0.05). A total of 611 and 973 genes of the adipose tissue were significantly up-regulated and down-regulated, respectively, in fish fed ARA (P < 0.05). Dietary ARA upregulated LOX pathway but downregulated CYP450 pathway annotated genes expression. A total of 65 cell development annotated genes including 30 adipocyte proliferation, 21 adipocyte differentiation, and 14 cell apoptosis annotated genes were down-regulated in the ARA group. In addition, 19 lipid catabolism annotated genes were increased. The mRNA expression levels of 5 chemokines, 10 cytokines, 26 cytokine and chemokine receptors, 15 cell adhesion, 6 oxidative stress, and 6 angiogenesis annotated genes were all down-regulated in fish fed ARA. Finally, dietary ARA also decreased the expression of transcripts annotated with glucose transportation, glycolysis and gluconeogenesis. Overall, our results demonstrate that dietary ARA has a fat reducing role, and tends to retard adipocyte development and attenuate chronic inflammation based on these adipose transcript expression results in grass carp.

488 - Tacrolimus Levels and Correlation to Age and Weight Calculation

Background: Tacrolimus (FK) has become one of the key calcineurin inhibitors routinely used to reduce the risk of graft-versus-host-disease in patients undergoing allogeneic stem cell transplant (SCT). As non-ablative regimens have increased the number of transplants in the geriatric population, the data from initial studies may not accurately reflect our current transplant patients. Although the mechanism of action in elderly patients is similar, the metabolism and tolerability may be different. The narrow therapeutic index, drug interactions, and metabolism via the CYP450 pathway present unique challenges to achieving therapeutic drug levels. Current dosing at our institution relies exclusively on actual body weight (ABW) without taking into account age, gender, serum albumin, and ideal body weight (IBW). With this retrospective study, we explore the impact these factors may have on tacrolimus serum concentrations and associated toxicities. Methods: We performed a chart review of patients over the age of 18 who received tacrolimus as part of their allogeneic SCT at our center between 2014 and 2017. The following variables were obtained from the medical records: age, gender, ABW, height, IBW, initial FK dose, serum albumin, and FK trough levels within the first 2 weeks. Patients who did not have FK levels drawn within 5 days of starting treatment, those who received concomitant CYP inhibitors without dose adjustment, and those who died within 30 days from SCT were excluded. Results: Ninety-five patients met the criteria of which 59 were males and 36 females. Forty-six patients were supratherapeutic at first trough and 76 were supratherapeutic at either the first, second, or third level. Of the patients with supratherapeutic levels, 34.2% had clinical toxicity (n = 26). Male patients (P = .0006) and patients over age 65 (P = .0399) were more likely to be supratherapeutic at first tacrolimus trough. After adjusting for age and gender, the odds of having a supratherapeutic FK trough were 3.1 times higher for every .5 mg increase with ABW dosing (when using IBW as baseline). Conclusions: The current patient population undergoing allogeneic SCT requires a revised strategy for optimal care. The data presented here suggests male gender and age over 65 are predictive of having a supratherapeutic first FK trough which may favor the use of a lower starting dose. Similarly, the higher supratherapeutic events in patients with a greater difference between ideal and actual weights hints at improved dosing when the IBW is used in overweight patients. Our study suggests that age, gender, and IBW should be factored into tacrolimus dosing to prevent overtreatment and toxicities. Further prospective studies are needed to confirm these observations.

Modulation of Cyp450, ALS1 and COX-2 signaling pathways induced by Candida albicans infection via novel antifungal agents

Although, fluconazole is widely used in clinical treatment as an antifungal drug, it recorded potential problems as resistance and intracellular accumulation. Female albino mice were injected with single ip dose of Candida albicans (1.5 × 106 CFU). Three weeks post treatment with fluconazole and two novel synthesized compounds [(2-(4-(Pyridin-2-yl) aminosulfonylphenylamino)-6-(naphthalen-2-yl)-4-(pyridin-2-yl) pyridine-3carbonitrile) and (2-(4-(Pyrimidin-2-yl) aminosulfonylphenylamino)-6-(naphthalen-2-yl)-4-(pyridine-2-yl)pyridine-3-carbonitrile) (13b & 14b, respectively)] in both low and high doses (50 mg/kg & 200 mg/kg), liver function and vaginal inflammation were assessed. Candida albicans significantly elevated serum alanine aminotransferase (ALT) and butrylcholinesterase (BCHE) as well as hepatic malondialdehyde (MDA). Molecular analysis confirmed a significant up-regulation in mRNA gene expression of Agglutinin-like sequence (ALS1), hepatic cytochrome p450 (Cyp450). Vaginal COX-2 gene expression was also elevated. Nevertheless, a significant down-regulation was apparent in mice treated with the aforementioned compounds. Meanwhile, administration of 14b in a high dose noticeably down-regulated the altered parameters expression showing a significant effect in comparison to animals treated with the variable doses of the tested compounds. Histopathological finding confirmed the obtained results. The current work investigated the efficiency of new synthetic pyrimidine derivatives 14bas anti-microbial agents and recommended to be improved and evaluated as a novel antifungal drug to overcome the emergence of resistance problem.

Recent advances in the prediction of non‐CYP450‐mediated drug metabolism

Computational models of drug metabolism prediction have focused mainly on cytochrome P450 enzymes, because drug–drug interactions, reactive metabolite formation, hepatotoxicity, idiosyncratic adverse drug interactions, and/or loss of efficacy of many drugs were the results of interactions with CYP450s. Metabolic regioselectivity and isoform specificity prediction models for CYP450‐catalyzed reactions have reached approximately 95% accuracy. Thus, a new drug candidate is less likely to show unexpected metabolic profile due to metabolism via CYP450 pathways. For such candidates, secondary metabolic Phase I and II enzymes are likely to play an expected (or unexpected) role in drug metabolism. The importance of flavin monooxygenases (FMOs), aldehyde and alcohol dehydrogenase, monoamine oxidase from the Phase I and UDP‐glucuronosyltransferase (UGT), sulfotransferase, glutathione S‐transferase, and methyltransferase from Phase II has increased and United States Food and Drug Administration guidelines on NDA have specific recommendations for in vitro and in vivo testing against these enzymes. Thus, there is an urgent requirement of reliable predictive models for drug metabolism catalyzed by these enzymes. In this review, we have classified drug metabolism prediction models (site of metabolism, isoform specificity, and kinetic parameter) for these enzymes into Phase I and II. When such models are unavailable, we discuss the Quantitative Structure Activity Relationship (QSAR), pharmacophore, docking, dynamics, and reactivity studies performed for the prediction of substrates and inhibitors. Recently published models for FMO and UGT are discussed. The need for comprehensive, widely applicable, sequential primary and secondary metabolite prediction is highlighted. Potential difficulties and future prospectives in the development of such models are discussed. WIREs Comput Mol Sci 2017, 7:e1323. doi: 10.1002/wcms.1323This article is categorized under: Structure and Mechanism &gt; Reaction Mechanisms and Catalysis Computer and Information Science &gt; Chemoinformatics Software &gt; Molecular Modeling

Dysregulation of lipidomic profile and antiviral immunity in response to hyaluronan in patients with severe asthma

Author(s): Sokolowska, Milena; Chen, Li-Yuan; Liu, Yueqin; Martinez-Anton, Asuncion; Logun, Carolea; Alsaaty, Sara; Cuento, Rosemarie A; Cai, Rongman; Sun, Junfeng; Quehenberger, Oswald; Armando, Aaron M; Dennis, Edward A; Levine, Stewart J; Shelhamer, James H

A Physiologically-Based Pharmacokinetic Model to Predict Human Fetal Exposure for a Drug Metabolized by Several CYP450 Pathways.

Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful. A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK). The model was developed in both non-pregnant and pregnant women, and all physiological and enzymatic changes that could impact nevirapine PK were taken into account. Transplacental parameters estimated from ex vivo human placenta perfusion experiments were included in this PBPK model. To validate the model, observed maternal and cord blood concentrations were compared with predicted concentrations, and the impact of fetal clearance on fetal PK was investigated. By implementing physiological changes, including CYP3A4, 2D6 and 2B6 inductions, we predicted a clearance increase of 21% in late pregnancy. The PBPK model successfully predicted the disposition for both non-pregnant and pregnant populations. Parameters obtained from the ex vivo experiments allowed the prediction of nevirapine concentrations that matched observed cord blood concentrations. The fetal-to-maternal area under the curve ratio (0-24h interval) was 0.77, and fetal metabolism had no significant effect on fetal PK. The PBPK approach is a useful tool for quantifying a priori the drug exposure of metabolized drugs during pregnancy, and can be applied to evaluate alternative dosing regimens to optimize drug therapy. This approach, including ex vivo human placental perfusion parameters, is a promising approach for predicting human fetal exposure.

Are We Getting the Best Return on Investment From Clinical Drug-Drug Interaction Studies?

Are We Getting the Best Return on Investment From Clinical Drug-Drug Interaction Studies?