P450 Isoenzymes Research Articles

Pharmacogenetic features of tramadol metabolism affecting the quality of postoperative analgesia in vascular surgery

BACKGROUND: The issue of the efficacy and safety of medications employed for postoperative analgesia has not been resolved to date. Insufficient analgesia constitutes one of the primary risk factors for developing cardiovascular complications postoperatively. Tramadol is a medication that is frequently used for postoperative pain relief following minor and moderately traumatic operations. The biotransformation of this drug is considerably slowed by the presence of CYP2D6 gene polymorphisms G1846A and C100T, which play a significant role in its metabolism. In such patients, a decrease in the quality of postoperative analgesia can be anticipated, which will consequently lead to an increase in cardiac complications. AIM: To assess the efficacy of a postoperative analgesia regimen based on tramadol and the incidence of cardiac complications during vascular operations depending on the presence/absence of polymorphisms of the CYP2D6 gene polymorphisms, an isoenzyme of cytochrome P-450. MATERIALS AND METHODS: An examination of 109 patients undergoing planned vascular surgery was conducted. The frequency of occurrence of polymorphisms G1846A and C100T of the CYP2D6 gene was determined. All patients were assessed for the severity of postoperative pain syndrome during activity and at rest using a visual analog scale on the first day following surgery. Cardiovascular complications that arose while the patients were in the hospital were documented. To assess the autonomic nervous system, patients underwent cardiointervalography. RESULTS: Polymorphism G1846A was detected in 28 (25.7%), while C100T was detected in four (3.7%) patients. Patients without polymorphisms were included in group 1 (n=77). Patients with polymorphisms were assigned to group 2 (n=32). Pain syndrome at rest and during activity was higher in group 2 patients (p 0.05). The tension index before surgery did not differ between the groups; however, it was greater in group 2 patients after surgery (p 0.001). Cardiac complications were identified in 9.1% of group 1 and 18.8% of group 2 patients (p=0.20). CONCLUSION: The frequency of polymorphisms G1846A and C100T of the CYP2D6 gene in patients who underwent vascular surgery was 29.4%. Such patients experienced pain syndrome of greater severity. The patient groups did not exhibit any significant differences in the frequency of cardiac complications.

ИЗГОТОВЛЕНИЕ ПЕЛЛЕТ КОФЕИНА МЕТОДОМ ЭКСТРУЗИИ-СФЕРОНИЗАЦИИ ДЛЯ «КОКТЕЙЛЬНОЙ» ТЕСТ-СИСТЕМЫ

Cocktail" test systems are used for phenotyping the metabolic activity of human cytochrome P450 isoenzymes. The vast majority of "cocktails" for phenotyping include caffeine, based on data on the metabolism of which the activity of the CYP1A2 isoenzyme is determined. The use of pellets as a dosage form consisting of many particles for "cocktail" test systems makes it easy to change the composition and dosage of the test system depending on the needs of CYP research, and also provides easier acceptance of the test system by the patient in geriatric studies. Aim. Development of pellets containing caffeine for a "cocktail" test system using the methodology of a complete factor experiment. Materials and methods. Pellets containing caffeine (Shandong Xinhua Pharmaceutical Co., Ltd., China) were manufactured by extrusion-spheronization in the ESI 25 apparatus (Tofflon, China). The obtained pellets were subjected to technological tests in accordance with the GF of the Russian Federation XV. The quality of the pellets obtained and their dissolution profile were evaluated. Results and discussion. With the help of a complete factorial experiment, the optimal composition of pellets was selected, the optimal amount of granulating liquid was selected, and the parameters of the extrusion-spheronization process were worked out. Conclusion. As a result of the conducted research, the composition and technology of production of caffeine pellets for the cocktail test system were developed using a complete factorial experiment. A technological scheme for the production of pellets has been developed. Optimal conditions for humidification of the pellet mass were selected for the extrusion-spheronization technology.

Paclitaxel Drug-Drug Interactions in the Military Health System.

Paclitaxel is an antineoplastic agent used to treat breast, lung, endometrial, cervical, pancreatic, sarcoma, and thymoma cancer. However, drugs that induce, inhibit, or are substrates of cytochrome P450 (CYP) isoenzymes 2C8 or 3A4 may alter the metabolism of paclitaxel, potentially impacting its effectiveness. The purposes of this study are to provide an overview of paclitaxel use, identify potential drugs that interact with paclitaxel, and describe their clinical manifestations. A retrospective analysis was performed on patients receiving paclitaxel to evaluate types and stages of cancer, treatment regimens, and adverse events of paclitaxel alone or paclitaxel in combination with other antineoplastic drugs, using data retrieved in March 2022 from the US Department of Defense Cancer Registry. Additionally, the study compared the health issues and prescriptions of patients who completed treatment with those who discontinued treatment. It evaluated interactions of paclitaxel with noncancer drugs, particularly antidepressants metabolizing and inhibiting CYP3A4, using data from the Comprehensive Ambulatory/Professional Encounter Record and the Pharmacy Data Transaction Service database. Data were retrieved in October 2022. Of 702 patients prescribed paclitaxel, 338 completed treatment. Paclitaxel discontinuation alone vs concomitantly (P < .001) and 1 drug vs combination (P < .001) both were statistically significant. Patients who took paclitaxel concomitantly with a greater number of prescription drugs had a higher rate of treatment discontinuation than those who received fewer medications. Patients in the completed group received 9 to 56 prescription drugs, and those in the discontinued group were prescribed 6 to 70. Those who discontinued treatment had more diagnosed medical issues than those who completed treatment. The study provides a comprehensive overview of paclitaxel usage from 1996 through 2022 and highlights potential drug interactions that may affect treatment outcomes. While the impact of prescription drugs on paclitaxel discontinuation is uncertain, paclitaxel and antidepressants do not have significant drug-drug interactions.

Drug-Cannabinoid Interactions in Selected Therapeutics for Symptoms Associated with Epilepsy, Autism Spectrum Disorder, Cancer, Multiple Sclerosis, and Pain.

Clinical practice entails a translation of research that assists in the use of scientific data and therapeutic evidence for the benefit of the patient. This review critically summarizes the potential impact of cannabinoids in conjunction with other drugs when associated with treatments for epilepsy, autism spectrum disorder, cancer, multiple sclerosis, and chronic pain. In these associations, potential drug interactions may occur and alter the predicted clinical results. Therefore, the potential for drug interactions must always be assessed to avoid therapeutic failures and/or increased side effects. Some effects may be additive, synergistic, or antagonistic, but changes in absorption, distribution, metabolism, particularly through cytochrome P450 (CYP) isoenzymes (e.g., CYP2C9 and CYP3A4), and excretion may also occur. For example, the combination of cannabis-derived compounds and the antifungal drug ketoconazole, a CYP3A4 inhibitor, increases the plasma concentration of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In contrast, rifampicin, a CYP3A4 inducer, stands out for reducing plasma THC levels by approximately 20-40% and 50% to 60% for CBD. Other CYP3A4 inhibitors and inducers are likely to have a similar effect on plasma concentrations if co-administered. Pharmacokinetic interactions with anticonvulsant medications have also been reported, as have pharmacodynamic interactions between cannabinoids and medications with sympathomimetic effects (e.g., tachycardia, hypertension), central nervous system depressants (e.g., drowsiness, ataxia), and anticholinergics (e.g., tachycardia and somnolence). Although further studies are still pending, there is currently clinical evidence supporting drug interactions with cannabinoids, requiring doctors to evaluate the risk of drug combinations with cannabinoids and vice versa. The tables provided here were designed to facilitate the identification of biorelevant interactions that may compromise therapeutic efficacy and toxicity.

Investigation of the drug–drug interaction and incompatibility mechanism between Aconitum carmichaelii Debx and Pinellia ternata (Thunb.) Breit

Ethnopharmacological relevanceThe combination of Aconitum carmichaelii Debx (Chuanwu, CW) and Pinellia ternata (Thunb.) Breit (Banxia, BX) forms an herbal pair within the eighteen incompatible medicaments (EIM), indicating that BX and CW are incompatible. However, the scientific understanding of this incompatibility mechanism, especially the corresponding drug–drug interaction (DDI), remains complex and unclear. Aim of the studyThis study aims to explain the DDI and potential incompatibility mechanism between CW and BX based on pharmacokinetics and cocktail approach. Materials and methodsUltraperformance liquid chromatography–tandem mass spectrometry methods were established for pharmacokinetics and cocktail studies. To explore the DDI between BX and CW, in the pharmacokinetics study, 10 compounds were determined in rat plasma after administering CW and BX–CW herbal pair extracts. In the cocktail assay, the pharmacokinetic parameters of five probe substrates were utilized to assess the influence of BX on cytochrome P450 (CYP) isoenzyme (dapsone for CYP3A4, phenacetin for CYP1A2, dextromethorphan for CYP2D6, tolbutamide for CYP2C9, and omeprazole for CYP2C19). Finally, the DDI and incompatibility mechanism of CW and BX were integrated to explain the rationality of EIM theory. ResultsBX not only enhances the absorption of aconitine and benzoylaconine but also accelerates the metabolism of mesaconitine, benzoylmesaconine, songorine, and fuziline. Moreover, BX affects the activity of CYP enzymes, which regulate the metabolism of toxic compounds. ConclusionsBX altered the activity of CYP enzymes, consequently affecting the metabolism of toxic compounds from CW. This incompatibility mechanism may be related to the increased absorption of these toxic compounds in vivo.

MOLECULAR DOCKING OF 4-AZIDO-2-(4-SUBSTITUTED-PHENYL)-5-(2-NITROPHENYL)-2H-1,2,3-TRIAZOLES

Molecular docking of 4-azido-2-(4-substituted-phenyl)-5-(2-nitrophenyl)-2H-1,2,3-triazoles was fulfilled by means of SwissADME prediction software and carried out analysis on P-glycoprotein and Cytochrome P450 isoenzymes as well as calculations of the pharmacokinetic properties of the compounds. 4-azido-2-(4-substituted-phenyl)-5-(2-nitrophenyl)-2H-1,2,3-triazole were considered as molecules which meet the requirements for the synthesis of medicinal substances. At the same time, by means of Swiss Targeted Prediction software were made calculations using the Brain or Intestine permeability method (BOILED-Egg) and obtained positive results.

Effects of microplastics on key reproductive and biochemical endpoints of the freshwater microcrustacean Daphnia magna

Human activities have directly impacted the environment, causing significant ecological imbalances. From the different contaminants resulting from human activities, plastics are of major environmental concern. Due to their high use and consequent discharge, plastics tend to accumulate in aquatic environments. There, plastics can form smaller particles (microplastics, MPs), due to fragmentation and weathering, which are more prone to interact with aquatic organisms and cause deleterious effects, including at the basis of different food webs. This study assessed the effects of two microplastics (polyethylene terephthalate, PET; and polypropylene, PP; both of common domestic use) in the freshwater cladoceran species Daphnia magna. Toxic effects were assessed by measuring reproductive traits (first brood and total number of offspring), and activities of biomarkers involved in xenobiotic metabolism (phase I: cytochrome P-450 isoenzymes CYP1A1, 1A2 and 3A4; phase II/conjugation: glutathione S-transferases; and antioxidant defense (catalase)). Both MPs showed a potential to significantly reduce reproductive parameters in D. magna. Furthermore, PET caused a significant increase in some isoenzymes of CYP450 in acutely exposed organisms, but this effect was not observed in chronically exposed animals. Similarly, the activity of the antioxidant defense (CAT) was significantly increased in acutely exposed animals, but not in chronically exposed organisms. This pattern of effects suggests a possible mechanism of long-term adaptation to the presence of the tested MPs. In conclusion, the herein tested MPs have shown the potential to induce deleterious effects on D. magna mainly observed in terms of the reproductive outcomes. Changes at the biochemical level seems transient and are not likely to occur in long term, environmentally exposed crustaceans.

The Frequency and Structure of Adverse Drug Reactions in the Pharmacotherapy of Epilepsy

The problem of the safety of antiepileptic therapy due to the duration of treatment and the need for regular intake of antiepileptic drugs (AEDs) is extremely significant. Adverse reactions (ADRs) may outweigh any positive effect of therapy associated with seizure reduction. The purpose of the study: to analyze the frequency and structure of ADRs of AEDs. Materials and Methods: The work was carried out within the framework of comprehensive research on the topic No. 210-16 "Epidemiological, genetic and neurophysiological aspects of diseases of the nervous system (central, peripheral and vegetative) and preventive medicine" (registration number 0120.0807480). Results: The frequency of ADRs against the background of third-generation AEDs was not inferior to that against the background of receiving second-generation AEDs, while the structure of ADRs was different: third-generation AEDs had a higher incidence of ADRs from the central nervous system, including a worsening of the course of epilepsy. The ratio of the chances of valproic acid accumulation with the achievement of toxic concentration in the blood and the development of un-desirable side effects in poor metabolizers (carriers of the polymorphism of CYP2C9*2 or CYP2C9*3) the gene encoding the cytochrome P450 isoenzyme 2C9 of the liver is 5.94 and 4.27, respectively. Conclusion: A personalized approach to ensuring the safety of valproic acid preparations based on taking into account the carriage of polymorphisms of the CYP2C9 gene allows to reduce the incidence of ADRs in patients receiving valproic acid preparations from 59.28% to 10.78%. The introduction of a personalized approach to the administration of valproates to patients suffering from epilepsy in the Krasnoyarsk Territory did not lead to an increase in direct costs.

The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients.

Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine. The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity. The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms. The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.

Features of lipid-lowering therapy in liver transplant recipients

Liver transplantation (LT) requires not only a carefully organized system for monitoring the condition of patients in the early postoperative period, but also reliable coordination of the actions of doctors of different specialties in the long-term period. This is due to improved survival of liver transplant recipients and a shift in the mortality structure towards cardiovascular diseases and the need to correct metabolic complications that often occur in recipients, in particular hyperlipidemia. Treatment of lipid metabolism disorders after LT includes lifestyle changes, immunosuppressive and lipid-lowering therapy (LLT), which reduces cardiovascular risk. The use of LLT in patients after LT is limited by potential side effects caused by drug interactions, in particular myopathy up to rhabdomyolysis. According to current clinical guidelines, the safest treatment for patients after LT is pravastatin and fluvastatin, the use of which is limited by low availability and low efficacy. It seems promisingto improve LLT in patients after LT through the use of ezetimibe, which has a potentially favorable tolerability profile when combined with immunosuppressants, as well as pitavastatin, which is metabolized through cytochrome P-450 isoenzymes not involved in the metabolism of immunosuppressants, and metabolically neutral PCSK9 inhibitors.

In silico Exploration of Pharmacological and Molecular Descriptor Properties of Salacinol and Its Related Analogues

Salacinol and its related analogues have been known for their potent α-glucosidase inhibitor activity and making them interesting candidates for a new type of anti-diabetic agent. Therefore, it is essential to investigate the physicochemical properties, pharmacological parameters, and toxicity profile of these anti-diabetic agents. In this study, a comprehensive in-silico approach was used to explore the absorption, distribution, metabolism, excretion, and toxicity profiles of salacinol and its related analogues. In addition, to gain a better knowledge of structural and electrical characteristics, global and local reactivity descriptors, and molecular electrostatic potential were calculated and discussed by using DFT at the B3LYP/6–311++G (d, p) level of theory. The results explored that all the studied compounds have low GI absorption and are substrates for P-glycoprotein. None of the compounds can cross the BBB, and none of the compounds are inhibitors of cytochrome P450 isoenzymes. We also found that all compounds have various potential to interact with a wide range of biological targets, including GPCRs, enzymes, ion channels, kinases, and nuclear receptors. Additionally, all compounds have low toxicity and are unlikely to cause any major health hazards in terms of hepatotoxicity, mutagenicity, cardiotoxicity, cytotoxicity, and immunotoxicity. The molecular electrostatic potential map shows that the negative potential sites are in electronegative oxygen atoms, while the positive potential sites are around the hydrogen atoms. The present study concludes that salacinol and its analogues might be a promising safe and effective candidate for the development of therapeutic drugs derived from natural sources. However, some of their properties should be considered in the context of drug development and tissue protection strategies.

Efficacy and tolerability of rufinamide in the treatment of Lennox–Gastaut syndrome (experience of the Svt. Luka’s Association of Medical Institutions)

Background. Lennox–Gastaut syndrome (LGS) is a classic developmental and epileptic encephalopathy with a debut in childhood, characterized by resistance to therapy, a severe course, and an unfavorable prognosis. Due to the existing difficulties in treatment of LGS, hopes are pinned on development of new antiepileptic drugs with fundamentally different mechanisms of action, aimed specifically at the treatment of this severe form of epilepsy.Rufinamide (Inovelon®) is a new antiepileptic drug registered in the Russian Federation for use in the adjunctive therapy of LGS in patients older than 1 year. The main mechanism of action of rufinamide is the restriction of neuronal discharges associated with the blocking effect on sodium channels (regulation of sodium channels activity by increasing duration of their inactive state), and stabilization of neuronal membranes. The drug has a number of advantages concernung pharmacokinetic parameters and efficacy (including a wide spectrum of antiepileptic activity, good oral absorption, absence of active metabolites, urinary excretion, low affinity for plasma proteins, biotransformation without cytochrome P450 isoenzymes, low risk of drug interactions) and fairly good tolerability. The daily dose of rufinamide varies from 600 mg (with simultaneous administration of valproate) to 1000 mg (if the patient does not take valproate) in children over 4 years of age with a body weight of less than 30 kg and up to 2200–3200 mg in children over 4 years of age with a body weight of more than 30 kg and in adults; in children under 4 years of age, the maximum daily dose in combination with valproate is 30 mg/kg, and without valproic acid – 45 mg/kg.Aim. To analyze the efficacy and tolerability of rufinamide in the treatment of epilepsy based on the long-term experience of using the drug in the Svt. Luka’s Association of Medical Institutions.Materials and methods. We observed 64 patients aged from 1.5 to 26 years (44 men, 20 women) treated with rufinamide (Inovelon®). Among them, the structural etiology LGS was diagnosed in 36 patients, the genetic and presumably genetic etiology LGS – in 28. In all cases, rufinamide was used in accordance with approved indications as an additional antiepileptic drug, more often in combination with valproate, topiramate, levetiracetam or lamotrigine. Titration of the drug was carried out according to the recommendations in the instructions for use, up to a therapeutic dose that ranged from 200 to 1600 mg/day (in most cases from 400 to 1200 mg/day), depending on age and concomitant therapy.Results and conclusion. Remission of all types of seizures was registered in 17 (26.6 %) patients, and a decrease in the incidence of seizures by more than 50 % was recorded in 28 (43.8 %) patients. Of them, 13 patients demonstrated reduction in seizures frequency by more than 75–90 % and remission of one of several types of seizures. In general, the therapeutic effect (reduction of seizures frequency by at least 50 %) was achieved in 45 (70.3 %) of 64 patients. A decrease in seizures frequency of by at least 50 % was observed in 8 (12.5 %) patients; in 10 (15.6 %) patients, rufinamide therapy was not effective; in 1 (1.56 %) case an aggravation of bilateral convulsive seizures was noted when rufinamide was administered.In most cases, rufinamide is well tolerated. Our patients had side effects in 10 (15.6 %) cases. Only in 2 (3.1 %) cases, rufinamide was withdrawn directly due to side effects (the reason for withdrawal in these cases was an allergic reaction and psychosis).The retention rate for therapy lasting 1 year or more is 65.6 % (42 of 64 patients).Thus, our data have demonstrated efficacy and good tolerability of rufinamide in treating epileptic seizures associated with LGS, confirming numerous literature data. However, in our analysis, a higher rate of seizure remission was obtained, although we have included patients with mainly resistant forms of epilepsy in the analysis.

Maternal obesity impacts fetal liver androgen signalling in a sex-specific manner

BackgroundMaternal obesity (MO) increases fetal androgen concentrations, the prevalence of macrosomia, and predisposes offspring to metabolic dysfunction in later life, especially males. These risks may be, in part, the result of increased liver-specific androgen signalling pathway activity in utero. Androgen signalling activity can be suppressed by androgen metabolism via cytochrome P450 (CYP) isoenzymes (CYP2B6, CYP3A) or through inhibition of the full-length androgen receptor (AR-FL) via the antagonistic isoform, AR-45. We hypothesised MO impairs CYP enzyme activity and AR-45 expression in male fetal livers, thereby enhancing activity of androgen signalling pathways. MethodsNine months prior to pregnancy, nulliparous female baboons were assigned to either ad libitum control or high fat diet. At 165 day (d) gestation (term, 180 d) fetal liver was collected (n = 6/sex/group). CYP activity was quantified using functional assays; subcellular AR expression was measured using Western blot. ResultsCYP2B6 and CYP3A activity, and nuclear expression of AR-45, was reduced in MO males only. Nuclear AR-45 expression was inversely related with fetal body weight of MO males only. ConclusionsReduced CYP2B6 and CYP3A activity in conjunction with decreased nuclear AR-45 expression may enhance liver androgen signalling in males from MO pregnancies, thereby increasing the risk of macrosomia, as well as metabolic dysfunction in later life.

Modulatory Effects of Mangiferin Isolated from Aquilaria Plants on Human Cytochrome P450 Enzyme (CYP) Activities In vitro and In silico Studies

Background: Mangiferin has been identified as one of the major active constituents of Aquilaria plants. It was reported to have several promising chemotherapeutic potentials. Our preliminary data suggested that Aquilaria plant water extracts inhibited several cytochrome P450 (CYP) isoenzymes in vitro. Objective: This study aimed to investigate the modulatory effects of mangiferin on six major drug metabolizing CYP enzymes including CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP3A4, and CYP3A5. Methods: The enzyme activities were measured using fluorescence-based assays and enzyme kinetic such as IC50 parameters and Ki values were calculated to evaluate inhibitory potencies and mechanisms. Moreover, for potent inhibitions, molecular docking studies were carried out to explore potential interactions of residues between mangiferin and CYP enzymes. Results: Our findings suggested that mangiferin could inhibit CYP2D6, CYP3A4, and CYP3A5 in vitro with IC50 values of 9.2, 8.7, and 4.3 μM, and Ki values of 3.8, 10.8, and 9.6 μM, in a non-competitive inhibition pattern. Molecular docking studies using AutoDock 4.2 identified potential residues contained in mangiferin that interacted with CYP2D6, CYP3A4, and CYP3A5, resulting in the observed inhibitory effects. Conclusion: Mangiferin should be used carefully, in particular, with conventional drugs metabolized mainly by CYP2D6, CYP3A4, and CYP3A5. Further in vivo studies are recommended to evaluate the clinical relevance of these inhibitions.

Abstract 15688: Association of Cytochrome P450 2C19 Polymorphism With Ischemic and Bleeding Risk in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

Introduction: CYP2C19 isoenzymes of cytochrome P450 impact the effect of clopidogrel. Guidelines recommend clopidogrel in addition to oral anticoagulation (OAC) in patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI). This study aimed to evaluate the association of CYP2C19 polymorphism with ischemic and bleeding risk in patients with AF undergoing PCI. Methods: Patients with AF and an indication for OAC were included in this two-center prospective cohort study up to 3 days after PCI. Carriers of ≥1 loss of function (LOF) allele CYP2C19*2 were classified as poor metabolisers (PM). Carriers of ≥1 gain of function allele (GOF) were defined as rapid metabolisers (RM). Normal metabolisers (NM) were defined as absence of LOF and GOF alleles. Primary outcome was defined as death, myocardial infarction, or stroke (MACE) at 6 months ±2 weeks. Secondary outcome was defined as non-major clinically relevant (NMCR) or major bleedings. Results: 283 patients were included in the study. Median age was 78 (interquartile range, IQR 72-82) years old and 204 (72%) were males. All patients received treatment with clopidogrel and OAC. 73 (26%) were PM, 108 (38%) were NM and 102 (36%) RM. The primary ischemic outcome occurred in 22 (8%) and the secondary outcome in 38 (13%) patients. PM status did not significantly associate with primary ischemic outcome (PM: 6 [8.2%] vs. NM+RM: 16 [7.6%]; odds ratio, OR 1.09 [95% confidence interval 0.41-2.89], p=0.805). RM status did not significantly associate with bleeding (RM: 14 [13.7%] vs. PM+NM: 24 [13.3%]; OR 1.04 [0.51-2.12], p=1.00). Bleeding rates tended to be lower for patients with PM status (major, NMCR, or minor bleeding: PM 12 [28.7%] vs. NM+RM 84 [40.0%]; 0.61 [0.34-1.07], p=0.09). Conclusions: This pilot study of patients with oral anticoagulation for atrial fibrillation and clopidogrel after PCI ruled out, with 95% confidence, a ≥3-fold increase of ischemic risk for carriers of ≥1 loss of function allele CYP2C19*2 compared with non-carriers. This study was underpowered to detect less pronounced associations. LOF-carrier status might protect from bleeding.

Bioavailability predictions, pharmacokinetics and drug-likeness of bioactive compounds from Andrographis paniculata using Swiss ADME

Abstract Background: Earlier research on Andrographis paniculata focused on documenting their bioactive compounds profiles and traditional use. Before making a drug-like substance prediction using information from in silico experimental models, the current work aimed to examine and analyze the ADMET properties. This study assessed the drug-likeness and ADMET characteristics of bioactive compounds from A. paniculata. Materials and Methods: The current study will be the first to use the free online tool Swiss ADME to report the ADME characteristics of A. paniculata. The ADME properties of 10 bioactive compounds from A. paniculata were screened, and the results were evaluated. Results: Six bioactive compounds were identified to have good gastrointestinal absorption and can penetrate the brain. These compounds include andrographolide, 14-Acetylandrographolide, Drf3188, Neoandrographolide, Isoandrographolide, and 3,19-O-diacetyl andrographolide. On the other hand, three of the bioactive compounds were found to show Ames mutagenicity: 19-O-Acetylandrographolide, 3,19-isopropylideneandrographolide, and 14-glycinylandrographolide hydrochloride. Except 5-Hydroxy-7,8-dimethoxyflavone, most of these substances do not serve as substrates for both P-glycoprotein (P-gp) and Cytochrome P-450 isoenzymes (CYP). Furthermore, all the compounds were found to pass the Lipinski rule of five, indicating their potential suitability as drug candidates. Conclusion: Swiss ADME has proven to be an effective, dependable, and straightforward method for determining the ADME characteristics of the bioactive compounds in A. paniculata. Based on the information, it was predicted that A. panicluata would be effective in managing the disease. To validate these findings, it is advisable to conduct further controlled experimental research exploring the bioactive compounds’ pharmacological effects.

CLOZAPINE INDUCED EXTRAPYRAMIDAL SYMPTOMS FOLLOWING ALCOHOL CONSUMPTION IN PATIENT WITH SCHIZOPHRENIA AND ALCOHOL DEPENDENCE SYNDROME: A CASE REPORT OF SIALORRHEA, ACUTE AKATHISIA AND DYSTONIA

Clozapine (CLZ), a second-generation or atypical antipsychotic, although not recommended as the first-line drug of choice in the treatment of schizophrenia and schizoaffective disorders; however, it is recommended in the treatment of Treatment-Resistant Schizophrenia and in schizophrenic patients to decrease the recurrent risk of suicidal behavior. For the cytochrome P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4, CLZ serves as a substrate. CLZ also exhibits drug-food interaction with alcohol leading to an increase in the risk of seizures and extrapyramidal symptoms. A case of a 36-year-old male patient with a known history of paranoid schizophrenia and alcohol dependence syndrome came with complaints of dystonia and hypersalivation 1 day following the consumption of alcohol after ingestion of tablet CLZ. After clinical pharmacist intervention, the doses were titrated and the patient improved gradually. With this, it can be postulated that the concomitant use of alcohol with CLZ can be a predisposing factor for drug toxicity in the patients and hence patients should be monitored and counseled to abstain from the use of alcohol while on CLZ therapy.

Cytochrome P450 2B6 6 distribution among Burkinabè population

Mutations affect the genes that encode certain cytochromes P450 (CYP450) isoenzymes that are responsible for metabolism of drugs. The aim of this study was to determine the frequency of CYP2B6 (516G&gt;T) SNP in the Burkinabè population. Genomic DNA extraction from blood was performed by GenJET® Genomic DNA according to the manufacturer’s instructions. Genotyping for the cytochrome P450 variant alleles was performed using predesigned primers. The amplification was carried out by PCR while the differentiation between the alleles was carried out after digestion with restriction enzymes by electrophoresis. The CYP2B6 c.516G&gt;T was successfully analyzed in 92,38% (291/315) of the study participants. Among the investigated individuals, the distribution of the major allele CYP2B6*G was 56% and the minor CYP2B6*T allele was 44%. The results obtained showed a prevalence of 56% for the G allele and 44% for the T allele. This was distributed as 31% for the GG genotype (reduced dosage required), 51% for the GT genotype (normal dosage range), and 18% for the TT genotype (high drug toxicity). The presence of the rapid and poor metabolizer phenotypes in the studied sample shows the need for additional studies to better assess their impact on Burkinabe people.

Effects of schisandra lignans on the absorption of protopanaxadiol-type ginsenosides mediated by P-glycoprotein and protopanaxatriol-type ginsenosides mediated by CYP3A4

Ethnopharmacological relevanceGinseng Radix et Rhizoma (GRR) and Schisandrae Chinensis Fructus (SCF) are frequently used as herb pairs in traditional herbal formulas especially for the synergetic beneficial effects on lung and heart. Shengmai-yin (SMY), a noted formula, was first published in the traditional Chinese medicine classic named Yixue Qiyuan written by Zhang Yuansu in the Jin Dynasty, and has been used for deficiency of both qi and yin, palpitation, shortness of breath and spontaneous sweating. In SMY, GRR, a sovereign herb, plays an essential role in tonifying lung and supplementing qi, and SCF as an adjuvant herb contributes to the effects of nourishing yin and promoting fluid production, both of which are traditionally used as invigorants in China, Korea, Japan, and Russia. However, the underlying compatibility mechanism of GRR-SCF has remained unknown. Aim of the studyIn order to explore the impact and underlying mechanism of schisandra chinensis extract (SCE) on the absorption of ginsenosides Rb1, Rc, Rb2 and Rd belonging to protopanaxdiol (PPD)-type and ginsenosides Rg1 and Re belonging to protopanaxtriol (PPT)-type, pharmacokinetic studies, molecular docking technique and single-pass intestinal perfusion (SPIP) experiment were conducted. Material and methodsPreliminarily, pharmacokinetic characteristics of ginseng extract (GE) in the presence and absence of SCE were studied. Thereafter, molecular docking was used to predict whether ginsenosides were P-glycoprotein (P-gp) or cytochrome P450 isoenzyme 3A4 (CYP3A4) substrates. Finally, the effects and underlying mechanism of SCE on the absorption of GE were further investigated by in situ SPIP experiment. ResultsOur findings indicated that SCE could increase exposure in vivo and the intestinal absorption of distinct ginsenosides. Additionally, we found that the PPD-type ginsenosides Rb1, Rc, Rb2, and Rd were substrates for P-gp, and the PPT-type ginsenosides Rg1 and Re were substrates for CYP3A4 rather than P-gp. SCE, which has been found with extensive inhibitory effects on P-gp and CYP3A4, could remarkably promote the intestinal absorption of ginsenosides Rg1, Re, Rb1, Rc, Rb2, and Rd, obtaining similar effects comparable with ketoconazole known as a classic dual inhibitor of P-gp and CYP3A4. ConclusionsThe study demonstrated that SCE could improve the absorption of GE, and revealed the underlying compatibility mechanism of GRR and SCF from the perspective of P-gp and CYP3A4-mediated interactions to some extent, which provided a certain scientific reference for the compatibility and clinical practice of GRR-SCF as common herb pairs in traditional prescriptions such as SMY. Moreover, this study also furnished a strategy for improving the oral bioavailability of different types of ginsenosides by drug combinations.

Pharmacokinetic Drug-Drug Interactions: A Systematic Review of the Cytochrome P450 (CYP) Isoenzyme 3A4

The cytochrome P450 (CYP) isoenzyme 3A4 or CYP3A4 is a major drug-metabolizing enzyme that has the potential to cause pharmacokinetic drug-drug interactions. Primary research studies have demonstrated CYP3A4-mediated drug-drug interactions through a variety of mechanisms. However, there has been no review during the last 10 years of pharmacokinetic drug-drug interactions mediated by CYP3A4 isoenzymes. It is necessary to systematically review the pharmacokinetic drug-drug interactions mediated by CYP3A4. Source review of articles were retrieved from the PubMed and Scopus databases. The preparation of keywords through the population, intervention, comparison, and outcomes (PICO) method written based on the Boolean operator. Reporting the results of the paper search is presented in the Prisma version 1 2020 flowchart. The risk of bias assessment used COHORT tools and Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tools. Data was analyzed narratively. Pharmacokinetic drug interactions are mediated by CYP3A4 through the mechanism of induction, activation, inhibition, and inactivation. Induction or activation of CYP3A4 can cause an increase in CYP3A4 expression, so that the drug is metabolized more quickly and has the potential to lose drug efficacy. Inhibition and inactivation of CYP3A4 causes plasma drug levels to increase and drug elimination time to last longer. CYP3A4 plays a major role in the bioactivation of drugs that cause hepatotoxicity through the formation of reactive metabolites. The use of drugs needs to be monitored to avoid pharmacokinetic drug interactions.