CYP3A4 Induction Research Articles

Cannabidiol and cannabidiolic acid: Preliminary in vitro evaluation of metabolism and drug-drug interactions involving canine cytochrome P-450, UDP-glucuronosyltransferase, and P-glycoprotein.

Phytocannabinoid-rich hemp extracts containing cannabidiol (CBD) and cannabidiolic acid (CBDA) are increasingly being used to treat various disorders in dogs. The objectives of this study were to obtain preliminary information regarding the in vitro metabolism of these compounds and their capacity to inhibit canine cytochrome P450 (CYP)-mediated drug metabolism and canine P-glycoprotein-mediated transport. Pure CBD and CBDA, and hemp extracts enriched for CBD and for CBDA were evaluated. Substrate depletion assays using pooled dog liver microsomes showed CYP cofactor-dependent depletion of CBD (but not CBDA) and UDP-glucuronosytransferase cofactor-dependent depletion of CBDA (but not CBD) indicating major roles for CYP and UDP-glucuronosytransferase in the metabolism of these phytocannabinoids, respectively. Further studies using recombinant canine CYPs demonstrated substantial CBD depletion by the major hepatic P450 enzymes CYP1A2 and CYP2C21. These results were confirmed by showing increased CBD depletion by liver microsomes from dogs treated with a known CYP1A2 inducer (β-naphthoflavone) and with a known CYP2C21 inducer (phenobarbital). Cannabinoid-drug inhibition experiments showed inhibition (IC50 = 4.6-8.1 μM) of tramadol metabolism via CYP2B11-mediated N-demethylation (CBD and CBDA) and CYP2D15-mediated O-demethylation (CBDA only) by dog liver microsomes. CBD and CBDA did not inhibit CYP3A12-mediated midazolam 1'-hydroxylation (IC50 > 10 μM). CBD and CBDA were not substrates or competitive inhibitors of canine P-glycoprotein. Results for cannabinoid-enriched hemp extracts were identical to those for pure cannabinoids. These in vitro studies indicate the potential for cannabinoid-drug interactions involving certain CYPs (but not P-glycoprotein). Confirmatory in vivo studies are warranted.

Potential pharmacokinetic interactions with concurrent use of herbal medicines and a ritonavir-boosted COVID-19 protease inhibitor in low and middle-income countries.

The COVID-19 pandemic sparked the development of novel anti-viral drugs that have shown to be effective in reducing both fatality and hospitalization rates in patients with elevated risk for COVID-19 related morbidity or mortality. Currently, nirmatrelvir/ritonavir (Paxlovid™) fixed-dose combination is recommended by the World Health Organization for treatment of COVID-19. The ritonavir component is an inhibitor of cytochrome P450 (CYP) 3A, which is used in this combination to achieve needed therapeutic concentrations of nirmatrelvir. Because of the critical pharmacokinetic effect of this mechanism of action for Paxlovid™, co-administration with needed medications that inhibit or induce CYP3A is contraindicated, reflecting concern for interactions with the potential to alter the efficacy or safety of co-administered drugs that are also metabolized by CYP3A. Some herbal medicines are known to interact with drug metabolizing enzymes and transporters, including but not limited to inhibition or induction of CYP3A and P-glycoprotein. As access to these COVID-19 medications has increased in low- and middle-income countries (LMICs), understanding the potential for herb-drug interactions within these regions is important. Many studies have evaluated the utility of herbal medicines for COVID-19 treatments, yet information on potential herb-drug interactions involving Paxlovid™, specifically with herbal medicines commonly used in LMICs, is lacking. This review presents data on regionally-relevant herbal medicine use (particularly those promoted as treatments for COVID-19) and mechanism of action data on herbal medicines to highlight the potential for herbal medicine interaction Herb-drug interaction mediated by ritonavir-boosted antiviral protease inhibitors This work highlights potential areas for future experimental studies and data collection, identifies herbal medicines for inclusion in future listings of regionally diverse potential HDIs and underscores areas for LMIC-focused provider-patient communication. This overview is presented to support governments and health protection entities as they prepare for an increase of availability and use of Paxlovid™.

ACTH more than 2000 pg/ml; is it immunoassay interference or another matter?

Starting rifampicin in patients with Addison’s disease or adrenal tuberculosis may precipitate an adrenal crisis as a result of the induction of CYP 3A4 which in turn leads to increased breakdown of cortisol. We report this rare phenomenon to increase awareness among healthcare professionals.

Pregnancy related hormones increase CYP3A mediated buprenorphine metabolism in human hepatocytes: a comparison to CYP3A substrates nifedipine and midazolam.

Introduction: Pregnancy increases the clearance of CYP3A4 substrate drugs and pregnancy-related hormones (PRHs) induce hepatic CYP3A4 expression and metabolism. However, it remains unclear to what extent the magnitude of PRH-evoked changes in hepatic CYP3A metabolism varies across multiple substrates. This study quantified the impact of PRHs on CYP3A protein concentrations and buprenorphine metabolism in human hepatocytes, and compared the magnitude of these effects to nifedipine and midazolam metabolism. Methods: Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to PRHs, administered in combination across a range of physiologically relevant concentrations, for 72h. Absolute protein concentrations of CYP3A4, CYP3A5, and CYP3A7 in SCHH membrane fractions were quantified by nanoLC-MS/MS, and norbuprenorphine (nor-BUP), dehydro-nifedipine (dehydro-NIF), and 1-hydroxy-midazolam (1-OH-MDZ) formation was evaluated. Results: Compared to control, PRH exposure increased CYP3A4, CYP3A7, and total CYP3A protein concentrations, but not CYP3A5 concentrations, and increased nor-BUP, dehydro-NIF, and 1-OH-MDZ formation in a concentration-dependent manner. The formation of nor-BUP, dehydro-NIF, and 1-OH-MDZ each positively correlated with PRH-mediated changes in total CYP3A protein concentrations. The PRH-evoked increase in nor-BUP formation was evident in all donors; however, the PRH induction of dehydro-NIF and 1-OH-MDZ formation was diminished in a hepatocyte donor with high basal CYP3A5 expression. Discussion: These findings demonstrate that PRHs increase buprenorphine, nifedipine, and midazolam metabolism in SCHH via induction of CYP3A4 and total CYP3A protein concentrations, and the magnitude of these effects vary across hepatocyte donors in a substrate-specific manner. These data provide insight into the contribution of PRH induction of CYP3A4 metabolism to increased buprenorphine clearance during pregnancy.

Managing Drug Interactions With Oral Anticancer Treatments.

The use of oral anticancer treatments is widespread and vital to modern cancer treatment. Novel oral chemotherapy and targeted therapy treatments continue to receive US Food and Drug Administration approval every year, making knowledge of these agents a necessity for practitioners working in oncology. Many oral anticancer agents are prone to drug interactions that can contribute to adverse effects and decrease therapy efficacy. Potential drug-drug interactions include (1) interactions with CYP3A4 inhibitors and inducers, (2) interactions related to gastric acid suppression, (3) interactions related to prolongation of the cardiac QT interval, (4) interactions related to anticoagulant medications, and (5) drug-food and drug-herb interactions. Identifying potential drug interactions and appropriately managing them is key to preventing adverse effects and ensuring maximum efficacy while on oral anticancer therapy. Management of adverse effects increases patient compliance, ensures medication safety, and allows patients to remain on therapy. This article discusses the mechanisms of interactions and types of interacting medications. Specific recommendations are discussed.

Daridorexant, an Orexin Receptor Antagonist for the Management of Insomnia.

Insomnia is a common sleep disorder that is diagnosed primarily by patients' subjective reported symptoms. Daridorexant is a new dual orexin receptor antagonist that was recently approved by Food and Drug Administration for insomnia characterized by difficulty falling asleep and/or maintaining sleep. The orexin neuropeptide signaling system plays a role in wakefulness, and blocking the wake-promoting neuropeptides results in diminished wake signaling, thus exerting a sedative effect using an entirely different mechanism of action than the classical sleep promoting agents. The drug has quick onset of action, high volume of distribution, and high protein binding. Pharmacokinetics and pharmacodynamic parameters were similar in patients of different sex and age and were not significantly affected by race, body size, or mild-to-moderate kidney impairment. Dose limitation to 25 mg in moderate liver impairment and no use in severe liver impairment are recommended. The drug undergoes hepatic CYP3A4 metabolism; thus, caution with strong CYP3A4 inhibitors and inducers is warranted. The drug was approved based on phase 3 trials involving study 1 and study 2. Study 1 noted daridorexant at doses of 25 and 50 mg demonstrated a statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time against placebo at months 1 and 3. Similarly in study 2, compared with placebo, the 25 mg dose demonstrated statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time at months 1 and 3. Treatment-emergent adverse events were similar for daridorexant and placebo, with nasopharyngitis and headache most frequently reported. Daridorexant is a novel agent with demonstrated efficacy in sleep onset and maintenance and decrease in daytime sedation. Preliminary results from a 1-year extension study note similar incidences of mild-to-moderate side effects as noted in previous trials. Further studies are needed to establish its place in the pharmacological treatment of insomnia.

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.

Pharmacokinetics and Drug-Drug Interaction of Ocedurenone (KBP-5074) in vitro and in vivo.

Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. This study evaluated the involvement of cytochrome P450 (CYP) isozymes and drug transporters in the biotransformation of ocedurenone, and whether ocedurenone inhibited or induced CYP enzymes and transporters. Clinical pharmacokinetic drug-drug interaction (DDI) of ocedurenone with CYP3A inhibitor and inducer were investigated in healthy volunteers. In vitro tests were conducted to determine which CYP enzymes were involved in ocedurenone's metabolism and whether ocedurenone inhibited or induced these CYP enzymes; ocedurenone substrate characteristics for efflux and uptake transporters and its inhibitory potential on major drug transporters were also assessed. A clinical DDI study was conducted in healthy volunteers to evaluate the effects of a strong CYP3A inhibitor (itraconazole) and inducer (rifampin) on ocedurenone's pharmacokinetics. The in vitro study showed that ocedurenone was primarily metabolized by CYP3A4 and that it did not inhibit CYP enzymes. Ocedurenone appeared to be a substrate of BCRP and P-gp efflux transporters and inhibited BCRP, BSEP, MDR1, MATE1 and 2-K, OATP1B1/3, and OCT1. The clinical DDI study showed that itraconazole reduced ocedurenone's oral clearance by 51% and increased area under the plasma concentration-time curve extrapolated to infinity(AUC0-inf) by104%, while rifampin increased its oral clearance by 6.4-fold and decreased plasma AUC0-inf by 84%. Ocedurenone was shown to be a CYP3A substrate, with no inhibition potential on major drug metabolizing CYP enzymes and transporters at clinical efficacious doses. Ocedurenone did not induce CYP1A2 and 3A4 activity in cultured human primary hepatocytes. Clinical DDI study indicated ocedurenone was well tolerated when administered as a single 0.5-mg dose both alone and with itraconazole or rifampin, and while itraconazole had a weak effect on ocedurenone's pharmacokinetics, rifampin had a significant effect reducing systemic exposures.

NEAT1_2 and DAZAP1, Paraspeckle Components, Interact with PXR to Negatively Regulate CYP3A4 Induction.

Human pregnane X receptor (PXR) is a major nuclear receptor that upregulates the expression of drug-metabolizing enzymes such as CYP3A4. In our recent study, it was revealed that PXR interacts with DAZ-associated protein 1 (DAZAP1), which is an essential component of the paraspeckle, a membraneless nuclear body, and the interaction was disassociated by rifampicin, a ligand of PXR. The purpose of this study was to clarify the roles of paraspeckles in PXR-mediated transcriptional regulation. Immunoprecipitation assays using PXR-overexpressing HepG2 (ShP51) cells revealed that PXR interacts with not only DAZAP1 but also NEAT1_2, a long noncoding RNA included in the paraspeckle, and that the interaction between PXR and NEAT1_2 was disassociated by rifampicin. These results suggest that PXR is trapped in paraspeckles and that the activation of PXR by its ligands facilitates its disassociation from paraspeckles. Induction of CYP3A4 by rifampicin was significantly enhanced by the knockdown of NEAT1_2 or DAZAP1 in ShP51 cells and their parental HepG2 cells. A luciferase assay using a plasmid containing the PXR response elements of CYP3A4 revealed that the increased CYP3A4 induction by siNEAT1_2 or siDAZAP1 was due to the increased transactivation by PXR. These results suggest that paraspeckles play a role in trapping nuclear PXR in the absence of the ligand to negatively regulate transactivation of its downstream gene. Collectively, this is the first study to demonstrate that the paraspeckle components NEAT1_2 and DAZAP1 negatively regulate CYP3A4 induction by PXR. SIGNIFICANCE STATEMENT: This study revealed that PXR interacts with paraspeckle components NEAT1_2 and DAZAP1 to suppress CYP3A4 induction by PXR, and the interaction is dissociated by PXR ligands. This finding provides a novel concept that paraspeckles formed by liquid-liquid phase separation potentially affect drug metabolism via negative regulation of PXR function.

Physiologically-based pharmacokinetic modeling to predict drug-drug interaction of enzalutamide with combined P-gp and CYP3A substrates

Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro studies. A clinical drug-drug interaction (DDI) study between enzalutamide and digoxin, a typical P-gp substrate, suggested enzalutamide has weak inhibitory effect on P-gp substrates. Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, are dual substrates of CYP3A4 and P-gp, and hence it is recommended to avoid co-administration of these DOACs with combined P-gp and strong CYP3A inducers. Enzalutamide’s net effect on P-gp and CYP3A for apixaban and rivaroxaban plasma exposures is of interest to physicians who treat patients for venous thromboembolism with prostate cancer. Accordingly, a physiologically-based pharmacokinetic (PBPK) analysis was performed to predict the magnitude of DDI on apixaban and rivaroxaban exposures in the presence of 160 mg once-daily dosing of enzalutamide. The PBPK models of enzalutamide and M2, a major metabolite of enzalutamide which also has potential to induce CYP3A and P-gp and inhibit P-gp, were developed and verified as perpetrators of CYP3A-and P-gp-mediated interaction. Simulation results predicted a 31% decrease in AUC and no change in Cmax for apixaban and a 45% decrease in AUC and a 25% decrease in Cmax for rivaroxaban when 160 mg multiple doses of enzalutamide were co-administered. In summary, enzalutamide is considered to decrease apixaban and rivaroxaban exposure through the combined effects of CYP3A induction and net P-gp inhibition. Concurrent use of these drugs warrants careful monitoring for efficacy and safety.

Futibatinib (Lytgobi®)

Futibatinib (Lytgobi®)

Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis.

In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC 0-8h ). We characterized the pharmacogenetics of these interactions. Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters. Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC 0-8h values similar to controls, while CYP2B6 poor metabolizers had AUC 0-8h values of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC 0-8h values similar to controls, while NAT2 slow acetylators had AUC 0-8h values 36% higher than controls. CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.

18F]DPA-714: Effect of co-medications, age, sex, BMI and TSPO polymorphism on the human plasma input function.

We aimed to assess the effect of concomitant medication, age, sex, body mass index and 18-kDa translocator protein (TSPO) binding affinity status on the metabolism and plasma pharmacokinetics of [18F]DPA-714 and their influence on the plasma input function in a large cohort of 201 subjects who underwent brain and whole-body PET imaging to investigate the role of neuroinflammation in neurological diseases. The non-metabolized fraction of [18F]DPA-714 was estimated in venous plasma of 138 patients and 63 healthy controls (HCs; including additional arterial sampling in 16 subjects) during the 90min brain PET acquisition using a direct solid-phase extraction method. The mean fraction between 70 and 90min post-injection ([18F]DPA-71470-90) and corresponding normalized plasma concentration (SUV70-90) were correlated with all factors using a multiple linear regression model. Differences between groups (arterial vs venous measurements; HCs vs patients; high- (HAB), mixed- (MAB) and low-affinity binders (LAB); subjects with vs without co-medications, females vs males were also assessed using the non-parametric Mann-Whitney or Kruskal-Wallis ANOVA tests. Finally, the impact of co-medications on the brain uptake of [18F]DPA-714 at equilibrium was investigated. As no significant differences were observed between arterial and venous [18F]DPA-71470-90 and SUV70-90, venous plasma was used for correlations. [18F]DPA-71470-90 was not significantly different between patients and HCS (59.7 ± 12.3% vs 60.2 ± 12.9%) despite high interindividual variability. However, 47 subjects exhibiting a huge increase or decrease of [18F]DPA-71470-90 (up to 88% or down to 23%) and SUV70-90 values (2-threefold) were found to receive co-medications identified as inhibitors or inducers of CYP3A4, known to catalyse [18F]DPA-714 metabolism. Comparison between cortex-to-plasma ratios using individual input function (VTIND) or population-based input function derived from untreated HCs (VTPBIF) indicated that non-considering the individual metabolism rate led to a bias of about 30% in VT values. Multiple linear regression model analysis of subjects free of these co-medications suggested significant correlations between [18F]DPA-71470-90 and age, BMI and sex while TSPO polymorphism did not influence the metabolism of the radiotracer. [18F]DPA-714 metabolism fell with age and BMI and was significantly faster in females than in males. Whole-body PET/CT exhibited a high uptake of the tracer in TSPO-rich organs (heart wall, spleen, kidneys…) and those involved in metabolism and excretion pathways (liver, gallbladder) in HAB and MAB with a strong decrease in LAB (-89% and -85%) resulting in tracer accumulation in plasma (4.5 and 3.3-fold increase). Any co-medication that inhibits or induces CYP3A4 as well as TSPO genetic status, age, BMI and sex mostly contribute to interindividual variations of the radiotracer metabolism and/or concentration that may affect the input function of [18F]DPA-714 and consequently its human brain and peripheral uptake. INFLAPARK, NCT02319382, registered December 18, 2014, retrospectively registered; IMABIO 3, NCT01775696, registered January 25, 2013, retrospectively registered; INFLASEP, NCT02305264, registered December 2, 2014, retrospectively registered; EPI-TEP, EudraCT 2017-003381-27, registered September 24, 2018.

Flucloxacillin is a weak inducer of CYP3A4 in healthy adults and 3D spheroid of primary human hepatocytes.

Flucloxacillin is a widely used antibiotic. It is an agonist to the nuclear receptor Pregnane X Receptor (PXR) that regulates the expression of cytochrome P450 (CYP) enzymes. Treatment with flucloxacillin reduces warfarin efficacy and plasma concentrations of tacrolimus, voriconazole, and repaglinide. We conducted a translational study to investigate if flucloxacillin induces CYP enzymes. We also investigated if flucloxacillin induces its own metabolism as an autoinducer. We performed a randomized, unblinded, two-period, cross-over, clinical pharmacokinetic cocktail study. Twelve healthy adults completed the study. They ingested 1 g flucloxacillin three times daily for 31 days, and we assessed the full pharmacokinetics of the Basel cocktail drugs on days 0, 10, and 28, and plasma concentrations of flucloxacillin on days 0, 9, and 27. 3D spheroid of primary human hepatocytes (PHH) were exposed to flucloxacillin (concentration range: 0.15-250 μM) for 96 hours. Induction of mRNA expression, protein abundance, and enzyme activity of CYP enzymes were assessed. Flucloxacillin treatment reduced the metabolic ratio of midazolam (CYP3A4), (geometric mean ratio (GMR) 10 days (95% confidence interval (CI)): 0.75 (0.64-0.89)) and (GMR 28 days (95% CI): 0.72 (0.62-0.85)). Plasma concentrations of flucloxacillin did not change during 27 days of treatment. Flucloxacillin caused concentration-dependent induction of CYP3A4 and CYP2B6 (mRNA, protein, and activity), CYP2C9 (mRNA and protein), CYP2C19 (mRNA and activity), and CYP2D6 (activity) in 3D spheroid PHH. In conclusion, flucloxacillin is a weak inducer of CYP3A4, which may lead to clinically relevant drug-drug interactions for some narrow therapeutic range drugs that are substrates of CYP3A4.

Management of Drug Interactions with Inducers: Onset and Disappearance of Induction on Cytochrome P450 3A4 and Uridine Diphosphate Glucuronosyltransferase 1A1 Substrates.

People living with HIV may present co-morbidities requiring the initiation and subsequently the discontinuation of medications with inducing properties. The time to reach maximal enzyme induction and to return to baseline enzyme levels has not been thoroughly characterized. The aim of this study was to evaluate the onset and disappearance of dolutegravir [uridine diphosphate glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A4 substrate] and raltegravir (UGT1A1 substrate) induction with strong and moderate inducers using physiologicallybased pharmacokinetic (PBPK) modeling. The predictive performance of the PBPK model to simulate dolutegravir and raltegravir pharmacokinetics and to reproduce the strength of induction was verified using clinical drug-drug interaction studies (steady-state induction) and switch studies (residual induction). The model was considered verified when the predictions were within 2-fold of the observed data. One hundred virtual individuals (50% female) were generated to simulate the unstudied scenarios. The results were used to calculate the fold-change in CYP3A4 and UGT1A1 enzyme levels upon initiation and discontinuation of strong (rifampicin) or moderate (efavirenz or rifabutin) inducers. The time for reaching maximal induction and subsequent disappearance of CYP3A4 induction was 14 days for rifampicin and efavirenz but 7 days for rifabutin. The distinct timelines for the moderate inducers relate to their different half-lives and plasma concentrations. The induction and de-induction processes were more rapid for UGT1A1. Our simulations support the common practice of maintaining the adjusted dosage of a drug for another 2 weeks after stopping an inducer. Furthermore, our simulations suggest that an inducer should be administered for at least 14 days before conducting interaction studies to reach maximal induction.

Sex- and lifestyle-related factors are associated with altered hepatic CYP protein levels in people diagnosed with mental disorders.

In this study, we used human postmortem tissue to investigate hepatic protein expression levels of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 by LC‒MS/MS in a population of people suffering from mental disorders (n=171). We report hepatic protein levels of these six CYP isoforms in 171 individuals in total, and define a focused population dataset of 116 individuals after excluding 55 samples due to low Microsomal Protein Per Gram of Liver (MPPGL) yield. Postmortem decay was most likely the reason for the low MPPGL yield in the 55 samples. In the focused population, we found women to have significantly higher protein levels of CYP3A4 than men in addition to decreased CYP3A4 protein levels among obese individuals. Furthermore, MPPGL was negatively correlated with body mass index (BMI). An increase in CYP1A2 protein levels was observed among smokers and increased CYP2E1 protein levels were observed among individuals with a history of alcohol abuse. Finally, individuals who received phenobarbital (CYP3A4 inducer) had significantly higher CYP3A4 levels. In conclusion, lifestyle-related factors prevalent among people suffering from mental disorders are associated with altered CYP protein levels which may alter drug metabolism and affect the efficacy of commonly prescribed drugs. Furthermore, this investigation demonstrates that postmortem hepatic tissue can be used to study how lifestyle and effectors affect hepatic CYP-levels in a large cohort of patients. Significance Statement Using a large number of postmortem hepatic tissue specimens (n=116) originating from the autopsy of individuals diagnosed with mental disorders, we were able to show that hepatic CYP-levels were affected by alcohol, smoking, BMI, and sex and that MPPGL was affected by BMI. Theses lifestyle-related changes may alter drug metabolism and affect the efficacy of commonly prescribed drugs. It is a novel approach to use a large postmortem cohort to investigate how lifestyle and effectors affect hepatic CYP-levels.

Rifampin – Risperidone and Divalproex Drug-drug Interaction: A Case Report

Rifampin is a potent hepatic cytochrome enzyme inducer, promoting the metabolism of many drugs. Here, we describe a case wherein rifampin-induced drug interactions affected the clinical improvement of a patient on psychiatric drugs for bipolar disorder. He was administered divalproex, risperidone, quetiapine, and clonazepam, along with anti-tuberculosis drugs HERZ, containing 600 mg rifampin. Despite taking 900 mg/day divalproex, his serum valproate levels were below 2 μg/ml, and his manic symptom persisted. Therefore, the antipsychotic risperidone (5 mg) was replaced with olanzapine (20 mg). Following this, his manic symptoms improved rapidly. Rifampin is a potent CYP3A and CYP2D6 inducer and is known to significantly reduce serum risperidone levels. Thus, even a high dose of risperidone did not induce a significant clinical effect, which was observed immediately after replacing with olanzapine. Therefore, drug interactions may have had a significant effect on clinical outcomes. Clinicians should be cognizant of drug interactions when treating psychiatric patients on rifampin therapy. The case has been sufficiently revised to protect the patient's personal information.

Influence of microplastic-associated biofilms on the bioavailability of a mixture of cadmium and benzo[a]pyrene by the analysis of biomarker gene expression in larval zebrafish

Microplastics (MPs, 1 µm – 5 mm) in aquatic environments undergo complex weathering transformations such as those induced by microbial colonization and biofilm formation, that affect their ability to interact with environmental contaminants (co-contaminants). In this study, the microbial composition of MP biofilms and its influence on the sorption and bioavailability of two co-contaminants with different physicochemistry, benzo[a]pyrene (B[a]P) and cadmium (Cd) in a mixture, were assessed. Aqueous-phase bioavailability was measured by assessment of biomarker gene expression for these toxicants (cytochrome P450 1A, cyp1a, and metallothionein 2, mt2, for B[a]P and Cd respectively) in larval zebrafish, Danio rerio. Significant induction of cyp1a and mt2 gene expression (p < 0.05) was observed after exposure to the mixture of Cd, B[a]P and MPs compared to joint exposure with individual contaminants and MPs. Significant changes in bioavailability for mt2 biomarker (p < 0.001) resulted after exposure to a Cd and B[a]P mixture with MPs compared to the same exposure without MPs. Biofilms significantly reduced bioavailability of B[a]P (cyp1a gene expression (p < 0.01)) but not Cd (mt2 gene expression) in the mixture with Cd and B[a]P (HDPE + BF + B[a]P + Cd) compared to the same treatment without biofilm (HDPE + B[a]P + Cd). Thus, compared to Cd, the biofilm could provide additional interactions with B[a]P, and new specific active sites on the MPs surface, that reduced B[a]P bioavailability. Additionally, the biofilm microbial community included hydrocarbon-degrading bacteria able to metabolize hydrophobic chemicals. These data indicated that in a mixture of co-contaminants, the biofilm selectively influenced their bioavailability and that the microbial composition of MPs biofilm may have played a key role in reducing B[a]P bioavailability. The results of this study highlight how in a complex exposure scenario characterized by a mixture of different co-contaminants, the polymer and chemical properties and micro-surroundings of the organisms may affect contaminants' bioavailability and/or exposure.

Effects of Exposure Timing on cyp1a Expression, PAH Elimination, and Lipid Utilization in Lumpfish Embryos Exposed to Produced Water.

Intentional discharges of produced water from oil production platforms to the marine environment contain a complex mixture of toxicants, including polycyclic aromatic hydrocarbons (PAHs). Early life stages of fish are highly sensitive to petrogenic exposure, and short-term exposure during critical periods of embryonic development may have detrimental effects on larvae health and survival. However, why different periods are more sensitive to exposure than others are not fully understood. Three identical exposure experiments (48 h, approx. 30 μg/L tPAH, sum 42 PAHs) on lumpfish (Cyclopterus lumpus) embryos were conducted where only exposure timing was varied: 0-48 h post fertilization (hpf, starting before chorion hardening), 36-84 hpf (starting after chorion hardening), and 240-288 hpf (during organogenesis). Total PAH (tPAH) uptake at the end of exposure was 5× higher when exposed during fertilization than when exposed late (during organogenesis). The first evidence of cyp1a induction in lumpfish during embryogenesis was observed after 84 hpf. Early exposure affected lipid droplet coagulation, indicating altered lipid utilization during embryogenesis. Although no significant impacts of exposure were observed on hatching success, hatching was delayed when exposed at the latest time point. This study shows that chorion properties, lipid content, biotransformation potential, and timing of produced water exposure during lumpfish embryogenesis affected PAH uptake and elimination.

Physiologically based pharmacokinetic modelling to predict drug–drug interactions for encorafenib. Part I. Model building, validation, and prospective predictions with enzyme inhibitors, inducers, and transporter inhibitors

Encorafenib, a potent BRAF kinase inhibitor undergoes significant metabolism by CYP3A4 (83%) and CYP2C19 (16%) and also a substrate of P-glycoprotein (P-gp). Because of this, encorafenib possesses potential for enzyme-transporter related interactions. Clinically, its drug–drug interactions (DDIs) with CYP3A4 inhibitors (posaconazole, diltiazem) were reported and hence there is a necessity to study DDIs with multiple enzyme inhibitors, inducers, and P-gp inhibitors. USFDA recommended clinical CYP3A4, CYP2C19, P-gp inhibitors, CYP3A4 inducers were selected and prospective DDIs were simulated using physiologically based pharmacokinetic modelling (PBPK). Impact of dose (50 mg vs. 300 mg) and staggering of administrations (0–10 h) on the DDIs were predicted. PBPK models for encorafenib, perpetrators simulated PK parameters within twofold prediction error. Clinically reported DDIs with posaconazole and diltiazem were successfully predicted. CYP2C19 inhibitors did not result in significant DDI whereas strong CYP3A4 inhibitors resulted in DDI ratio up to 4.5. Combining CYP3A4, CYP2C19 inhibitors yielded DDI equivalent CYP3A4 alone. Strong CYP3A4 inducers yielded DDI ratio up to 0.3 and no impact of P-gp inhibitors on DDIs was observed. The DDIs were not impacted by dose and staggering of administration. Overall, this work indicated significance of PBPK modelling for evaluating clinical DDIs with enzymes, transporters and interplay.