Cytochrome P450 2C9 Research Articles

Retrospective evaluation of drug to drug interactions with paclitaxel use in military health.

e24118 Background: Paclitaxel is an antineoplastic agent used in the management of multiple metastatic and non-resectable tumor types approved for ovarian, breast, AIDS-related Kaposi sarcoma, non-small cell lung, pancreatic, cervical, endometrial, and thymoma or thymic carcinoma cancer by the US Food and Drug Administration. Cytochrome P450 (CYP) 3A4 or 2C8 inducers, inhibitors, or substrates may alter paclitaxel metabolism. Because DDIs can have an effect on clinical outcomes, we aimed to identify drugs that interact with paclitaxel and describe their clinical manifestations. Methods: A retrospective analysis was performed on the health records of patients in the US Department of Defense Cancer Registry (retrieved March 2022), Comprehensive Ambulatory/Professional Encounter Records, and Pharmacy Data Transaction Service database (both retrieved October 2022). Patients’ medical history, diagnoses, and demographics were extracted and analyzed for differences in adverse effects when these agents were used alone vs concomitantly with other prescription drugs. Patients’ diagnoses and prescription drug use were extracted to compare completed vs discontinued treatment groups, identify medications commonly co-administered with paclitaxel, and evaluate DDIs with antidepressants. Results: Of 702 patients using paclitaxel, 338 completed treatments. The P value for paclitaxel discontinuation when used alone vs concomitantly or 1 drug (alone or before or after) vs combination (2 to 4 drugs) was < .001. 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. Conclusions: This review cannot conclude that concomitant use with prescription drug(s) resulted in paclitaxel discontinuation. There were no significant DDIs determined between paclitaxel and antidepressants.[Table: see text]

Structural and biophysical analysis of cytochrome P450 2C9*14 and *27 variants in complex with losartan

The human cytochrome P450 (CYP) 1, 2 and 3 families of enzymes are responsible for the biotransformation of a majority of the currently available pharmaceutical drugs. The highly polymorphic CYP2C9 predominantly metabolizes many drugs including anticoagulant S-warfarin, anti-hypertensive losartan, anti-diabetic tolbutamide, analgesic ibuprofen, etc. There are >80 single nucleotide changes identified in CYP2C9, many of which significantly alter the clearance of important drugs. Here we report the structural and biophysical analysis of two polymorphic variants, CYP2C9*14 (Arg125His) and CYP2C9*27 (Arg150Leu) complexed with losartan. The X-ray crystal structures of the CYP2C9*14 and *27 illustrate the binding of two losartan molecules, one in the active site near heme and another on the periphery. Both losartan molecules are bound in an identical conformation to that observed in the previously solved CYP2C9 wild-type complex, however, the number of losartan differs from the wild-type structure, which showed binding of three molecules. Additionally, isothermal titration calorimetry experiments reveal a lower binding affinity of losartan with *14 and *27 variants when compared to the wild-type. Overall, the results provide new insights into the effects of these genetic polymorphisms and suggests a possible mechanism contributing to reduced metabolic activity in patients carrying these alleles.

Physiologically based pharmacokinetic modeling of CYP2C8 substrate rosiglitazone and its metabolite to predict metabolic drug-drug interaction

Rosiglitazone is an activator of nuclear peroxisome proliferator-activated (PPAR) receptor gamma used in the treatment of type 2 diabetes mellitus. The elimination of rosiglitazone occurs mainly via metabolism, with major contribution by enzyme cytochrome P450 (CYP) 2C8. Primary routes of rosiglitazone metabolism are N-demethylation and hydroxylation. Modulation of CYP2C8 activity by co-administered drugs lead to prominent changes in the exposure of rosiglitazone and its metabolites. Here, we attempt to develop mechanistic parent-metabolite physiologically based pharmacokinetic (PBPK) model for rosiglitazone. Our goal is to predict potential drug-drug interaction (DDI) and consequent changes in metabolite N-desmethyl rosiglitazone exposure. The PBPK modeling was performed in the PKSim® software using clinical pharmacokinetics data from literature. The contribution to N-desmethyl rosiglitazone formation by CYP2C8 was delineated using vitro metabolite formation rates from recombinant enzyme system. Developed model was verified for prediction of rosiglitazone DDI potential and its metabolite exposure based on observed clinical DDI studies. Developed model exhibited good predictive performance both for rosiglitazone and N-desmethyl rosiglitazone respectively, evaluated based on commonly acceptable criteria. In conclusion, developed model helps with prediction of CYP2C8 DDI using rosiglitazone as a substrate, as well as changes in metabolite exposure. In vitro data for metabolite formation can be successfully utilized to translate to in vivo conditions.

Modeled Hepatic/Plasma Exposures of Omeprazole Prescribed Alone in Cytochrome P450 2C19 Poor Metabolizers Are Likely Associated with Hepatic Toxicity Reported in a Japanese Adverse Event Database.

Omeprazole, a gastric acid pump inhibitor, is repeatedly administered and is oxidatively metabolized mainly by polymorphic cytochrome P450 2C19. The prescribed dosage of omeprazole was discontinued or reduced in 47 of the 135 patients who received omeprazole alone in this survey, as recorded in the Japanese Adverse Drug Event Report database. The days to onset of omeprazole-related disorders were 3-4 d (median) and 16 d for intravenous 20-40 mg and oral 20 mg daily doses, respectively, in 34 patients for whom relevant data were available. The maximum plasma concentration of omeprazole was pharmacokinetically modeled after a single oral 40-mg dose in P450 2C19-defective poor metabolizers and was 2.4-fold higher than that in extensive metabolizers. The modeled area under the hepatic concentration curves of omeprazole in P450 2C19 poor metabolizers after virtual daily 40-mg doses for 7 d was 5.2-fold higher than that in the extensive metabolizers. Omeprazole-induced P450 2C19 (approx. 2-fold), resulting in increased hepatic intrinsic clearance in repeated doses, was considered after the second day. Virtual plasma/hepatic exposure estimated using pharmacokinetic modeling in subjects with P450 2C19 poor metabolizers indicated that these exposure levels virtually estimated could be one of causal factors for unexpected hepatic disorders induced by prescribed omeprazole, such as those resulting from drug interactions with repeatedly co-administered medicines.

The Cytochrome P450 2C8*3 Variant (rs11572080) Is Associated with Improved Asthma Symptom Control in Children and Altered Lipid Mediator Production and Inflammatory Response in Human Bronchial Epithelial Cells.

This study investigated an association between the cytochrome P450 (CYP) 2C8*3 polymorphism with asthma symptom control in children and changes in lipid metabolism and pro-inflammatory signaling by human bronchial epithelial cells (HBECs) treated with cigarette smoke condensate (CSC). CYP genes are inherently variable in sequence, and while such variations are known to produce clinically relevant effects on drug pharmacokinetics and pharmacodynamics, the effects on endogenous substrate metabolism and associated physiologic processes are less understood. In this study, CYP2C8*3 was associated with improved asthma symptom control among children: Mean asthma control scores were 3.68 (n = 207) for patients with one or more copies of the CYP2C8*3 allele versus 4.42 (n = 965) for CYP2C8*1/*1 (P = 0.0133). In vitro, CYP2C8*3 was associated with an increase in montelukast 36-hydroxylation and a decrease in linoleic acid metabolism despite lower mRNA and protein expression. Additionally, CYP2C8*3 was associated with reduced mRNA expression of interleukin-6 (IL-6) and C-X-C motif chemokine ligand 8 (CXCL-8) by HBECs in response to CSC, which was replicated using the soluble epoxide hydrolase inhibitor, 12-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]-dodecanoic acid. Interestingly, 9(10)- and 12(13)- dihydroxyoctadecenoic acid, the hydrolyzed metabolites of 9(10)- and 12(13)- epoxyoctadecenoic acid, increased the expression of IL-6 and CXCL-8 mRNA by HBECs. This study reveals previously undocumented effects of the CYP2C8*3 variant on the response of HBECs to exogenous stimuli. SIGNIFICANCE STATEMENT: These findings suggest a role for CYP2C8 in regulating the epoxyoctadecenoic acid:dihydroxyoctadecenoic acid ratio leading to a change in cellular inflammatory responses elicited by environmental stimuli that exacerbate asthma.

Evaluation of the Clinical Drug-Drug Interaction Potential of Pritelivir on Transporters and CYP450 Enzymes Using a Cocktail Approach.

Pritelivir is a novel viral helicase-primase inhibitor active against herpes simplex virus. In vitro drug-drug interaction studies indicated that pritelivir has the potential for clinically relevant interactions on the cytochrome P450 (CYP) enzymes 2C8, 2C9, 3A4, and 2B6, and intestinal uptake transporter organic anion transporting polypeptide (OATP) 2B1 and efflux transporter breast cancer resistance protein (BCRP). This was evaluated in 2 clinical trials. In 1 trial the substrates flurbiprofen (CYP2C9), bupropion (CYP2B6), and midazolam (CYP3A4) were administered simultaneously as part of the Geneva cocktail, while the substrate celiprolol (OAPT2B1) was administered separately. In another trial, the substrates repaglinide (CYP2C8) and rosuvastatin (BCRP) were administered separately. Exposure parameters of the substrates and their metabolites (flurbiprofen and bupropion only) were compared after administration with or without pritelivir under therapeutic concentrations. The results of these trials indicated that pritelivir has no clinically relevant effect on the exposure of substrates for the intestinal uptake transporter OATP2B1 and the CYP enzymes 3A4, 2B6, 2C9, and 2C8, and has a weak inhibitory effect on the intestinal efflux transporter BCRP. In summary, the results suggest that pritelivir has a low drug-drug interaction potential.

Efficacy of prasugrel versus clopidogrel for early neurological deterioration in branch atheromatous disease: An exploratory study

AbstractBackgroundDual antiplatelet therapy (DAPT) with clopidogrel is one of the initial treatment regimens for early neurological deterioration (END) in branch atheromatous disease (BAD). However, its effectiveness is affected by cytochrome P450 2C19 polymorphism. Prasugrel, with reduced cytochrome P450 2C19 interactions, has been approved for cerebrovascular diseases in Japan.AimTo explore the efficacy of DAPT with prasugrel and with clopidogrel in preventing END.MethodsPatients with BAD, admitted within 48 h of symptom onset between June 2022 and September 2023, were enrolled. The primary endpoint was the proportion of patients with END within 7 days, which was defined as an increase of 1 point or more on the National Institutes of Health Stroke Scale (NIHSS). Patients meeting specific magnetic resonance imaging (MRI) criteria, including lesions of ≥15 mm in the lenticulostriate artery (LSA) region or infarcts extending to the ventral side of the paramedian pontine region, were included. The patients were randomly assigned to the clopidogrel with loading and prasugrel without loading groups and administered common medications.ResultsThe study included 9 and 10 patients in clopidogrel and prasugrel groups, of whom 56% and 50% had END, respectively. The prasugrel group had earlier exacerbations after admission (days 0–1) than that of the clopidogrel group (days 1–2). The bleeding complications of both groups were not significantly different.ConclusionThe two groups had similar proportions of patients with END, suggesting comparable efficacies of both drugs for patients with BAD.

Early evaluation of a novel alert within cardiac procedural areas to facilitate genotype‐guided antiplatelet therapy

AbstractIntroductionClopidogrel remains widely utilized in patients undergoing percutaneous coronary intervention despite compelling evidence that genetic variation impacts patient response to clopidogrel. Clinical decision support (CDS) is frequently used to aid in precision medicine; however, limitations within the electronic medical record can hinder reliable CDS. Procedural areas where standard order entry is not utilized create a barrier to CDS implementation.ObjectivesWe aimed to evaluate the implementation of a novel alerting mechanism on genotype‐guided antiplatelet prescribing within the cardiac catheterization laboratory procedural setting.MethodsA retrospective cohort study was conducted to assess the rate of antiplatelet ordering in patients with one or two loss‐of‐function cytochrome P450 2C19 (CYP2C19) alleles before and after alert implementation. Pharmacogenomic congruence was measured before and after the alert via chart abstraction that included the CYP2C19 genotype and antiplatelet medications ordered within that encounter.ResultsA total of 236 patients were included in analyses, 127 encounters within the cohort before alert implementation and 136 encounters in the cohort after alert implementation. Prior to alert implementation, 40.9% (n = 127) were prescribed clopidogrel compared with 25.7% (n = 136) post implementation. After implementing a genotype‐guided alert within the cardiac catheterization laboratory procedural setting, providers were 2.22 times more likely to prescribe an alternative antiplatelet (p = 0.024). Clopidogrel‐naïve patients were 9.75 times more likely to receive a genotype‐guided antiplatelet order following alert implementation (p < 0.05).ConclusionProviders were responsive to a novel alert within the cardiac catheterization laboratory procedural setting. Genotype‐guided antiplatelet prescribing significantly increased following the alert implementation.

Recommendation of mavacamten posology by model-based analyses in adults with obstructive hypertrophic cardiomyopathy.

Mavacamten is the first cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). The phase III EXPLORER-HCM (NCT03470545) study used a dose-titration scheme based on mavacamten exposure and echocardiographic assessment of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Using population pharmacokinetic/exposure-response modeling and simulations of virtual patients, this in silico study evaluated alternative dose-titration regimens for mavacamten, including regimens that were guided by echocardiographic measures only. Mavacamten exposure-response models for VLVOTg (efficacy) and LVEF (safety) were developed using patient data from five clinical studies and characterized using nonlinear mixed-effects models. Simulations of five echocardiography-guided regimens were performed in virtual cohorts constructed based on either expected or equal population distributions of cytochrome P450 2C19 (CYP2C19) metabolizer phenotypes. Each regimen aimed to maximize the proportions of patients who achieved a VLVOTg below 30 mm Hg while maintaining LVEF above 50% over 40 weeks and 104 weeks, respectively. The exposure-response models successfully characterized mavacamten efficacy and safety parameters. Overall, the simulated regimen with the optimal benefit-risk profile across CYP2C19 phenotypes had steps for down-titration at weeks 4 and 8 (for VLVOTg <20 mm Hg), and up-titration at week 12 (for VLVOTg ≥30 mm Hg and LVEF ≥55%), and every 12 weeks thereafter. This simulation-optimized regimen is recommended in the mavacamten US prescribing information.

Risk Phenotypes, Comorbidities, Pharmacotherapy, and Electroconvulsive Therapy (ECT) in a Cohort with Difficult-to-Treat Depression in Comparison to an Unmedicated Control Group.

Approximately 15-25% of depressed patients suffer from difficult-to-treat depression (DTD). Patients with DTD require a thorough examination to avoid the oversight of treatable (psychiatric/somatic) comorbidities or (pseudo-)resistance to antidepressant drugs (ADs). Polymorphisms of the cytochrome P450 (CYP) enzymes 2D6 and 2C19, which play a major role in the metabolism of ADs, may contribute to resistance to ADs. Patients with DTD might benefit from electroconvulsive therapy (ECT). We enrolled 109 patients with DTD and 29 untreated depressed controls (UDC). We assessed risk phenotypes, comorbidities, and treatment, including ECT. We also performed pharmacokinetic analyses of CYP2D6 and CYP2C19. DTD patients significantly more often suffered from comorbid psychiatric diseases, especially ICD-10: F40-F48 (DTD:40.4%, UDC:17.2%, OR 11.87, p=0.011) than UDC patients. DTD patients receiving ECT were more likely to achieve remission (37.7% vs. 11.8%, OR=3.96, p=0.023). Treatment with ADs did not differ between remitters and non-remitters. No significant differences were observed in the distribution of CYP2D6 and CYP2C19 variants between both groups. Patients with DTD appear to experience comorbid neurotic stress and somatoform disorders (ICD-10: F40 - F48) more frequently. Therefore, a comprehensive differential diagnosis is crucial when patients do not respond sufficiently to antidepressant medication. Genotyping CYP2D6 and CYP2C19 should be considered.

A genetic algorithm-based approach for the prediction of metabolic drug-drug interactions involving CYP2C8 or CYP2B6

Background and objectivesA genetic algorithm (GA) approach was developed to predict drug-drug interactions (DDIs) caused by cytochrome P450 2C8 (CYP2C8) inhibition or cytochrome P450 2B6 (CYP2B6) inhibition or induction. Nighty-eight DDIs, obtained from published in vivo studies in healthy volunteers, have been considered using the area under the plasma drug concentration–time curve (AUC) ratios (i.e., ratios of AUC of the drug substrate administered in combination with a DDI perpetrator to AUC of the drug substrate administered alone) to describe the extent of DDI. MethodsThe following parameters were estimated in this approach: the contribution ratios (CRCYP2B6 and CRCYP2C8, i.e., the fraction of the dose metabolized via CYP2B6 or CYP2C8, respectively) and the inhibitory or inducing potency of the perpetrator drug (IRCYP2B6, IRCYP2C8 and ICCYP2B6, for inhibition of CYP2B6 and CYP2C8, and induction of CYP2B6, respectively). The workflow consisted of three main phases. First, the initial estimates of the parameters were estimated through GA. Then, the model was validated using an external validation. Finally, the parameter values were refined via a Bayesian orthogonal regression using all data. ResultsThe AUC ratios of 5 substrates, 11 inhibitors and 19 inducers of CYP2B6, and the AUC ratios of 19 substrates and 23 inhibitors of CYP2C8 were successfully predicted by the developed methodology within 50–200% of observed values. ConclusionsThe approach proposed in this work may represent a useful tool for evaluating the suitable doses of a CYP2C8 or CYP2B6 substrates co-administered with perpetrators.

Utility of the ACD-GENE-CLI Score in Asian Patients with Critical Limb Ischemia Undergoing Endovascular Interventions.

Critical limb ischemia (CLI) is an emerging public health threat and lacks a reliable score for predicting the outcomes. The Age, Body Mass Index, Chronic Kidney Disease, Diabetes, and Genotyping (ABCD-GENE) risk score helps identify patients with coronary artery disease who have cytochrome P450 2C19 (CYP2C19) polymorphism-related drug resistance and are at risk for cardiovascular adverse events. However, its application to CLI remains unknown. In this study, we aim to validate a modified ACD-GENE-CLI score to improve the prediction of major adverse limb events (MALEs) in patients with CLI receiving clopidogrel. Patients with CLI receiving clopidogrel post-endovascular intervention were enrolled prospectively in two medical centers. Amputation and revascularization as MALEs were regarded as the outcomes. A total of 473 patients were recruited, with a mean follow-up duration of 25 months. Except for obesity, old age, diabetes, chronic kidney disease (CKD), and CYP2C19 polymorphisms were significantly associated with MALEs. Using bootstrap regression analysis, we established a modified risk score (ACD-GENE-CLI) that included old age (≥ 65 years), diabetes, CKD, and CYP2C19 polymorphisms. At a cutoff value of 8, the ACD-GENE-CLI score was superior to the CYP2C19 deficiency only, and the conventional ABCD-GENE score in predicting MALEs (area under the curve: 0.69 vs. 0.59 vs. 0.67, p=0.01). The diagnostic ability of the ACD-GENE-CLI score was consistent in the external validation. Also, Kaplan-Meier curves showed that in CYP2C19 deficiency, the ABCD-GENE and ACD-GENE-CLI scores could all differentiate patients with CLI who are free from MALEs. The modified ACD-GENE-CLI score could differentiate patients with CLI receiving clopidogrel who are at risk of MALEs. Further studies are required to generalize the utility of the score.

CYP450 Inhibition on Cerebral Hemodynamics in Healthy, Young Males and Females During Simulated Hypovolemia

Animal models have shown that cytochrome P450 2C9 (CYP450) is involved in vascular control within the cerebrovasculature. However, the role sex plays on CYP450 within human cerebral circulation has not been examined. PURPOSE: To determine the contribution of CYP450 to cerebrovascular hemodynamics between healthy young males and females at rest and during mild simulated hypovolemia. METHODS: 18 subjects (9 females, tested during days 1-5 of early follicular phase) participated in 1 familiarization and 2 experimental visits. During experimental visits, subjects ingested a CYP450 inhibitor (fluconazole, FLZ 150mg) or placebo (PLC, 250mg microcrystalline cellulose) in a randomized, single-blind, crossover design. Following ingestion and 120 minutes of supine rest, middle cerebral artery velocity (MCAv, cm/s, Transcranial Doppler) and mean arterial pressure (MAP, mmHg, finger photoplethysmography) were continuously measured during 5 minutes of supine rest and 5 minutes of lower-body negative pressure (LBNP, -20mmHg). Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. RESULTS: Means ± SD. Resting values for all variables were not different between treatments (p &gt; 0.05). Therefore, all data are presented as a change (Δ) from rest to LBNP. There was no treatment*time*sex effect for MCAv or CVCi (p = 0.52, pη2 = 0.08; p = 0.34, pη2 = 0.06, respectively). MCAv responded similarly to LBNP between sexes within PLC and FLZ with a low-to-moderate effect (M -4.2 ± 5.2 vs. F -2.4 ± 7.3, p = 0.63, r = 0.11; M -4.2 ± 6.2 vs. F -8.1 ± 6.3, p = 0.06, r = 0.45, respectively). Similarly, male and female CVCi responses to LBNP were similar within treatments with a low effect (PLC M -0.04 ± 0.05 vs. -0.02 ± 0.08, p = 0.69, r = 0.09; FLZ M -0.06 ± 0.06 vs. -0.08 ± 0.05, p = 0.31, r = 0.24). Two one-sided testing (TOST) analysis, used to assess equivalence between groups (1), revealed that the differences between PLC and FLZ ΔMCAv and ΔCVCi were non-equivalent between the sexes (Mean = 5.67, t(13.84) = 0.42, p = 0.55; Mean = 0.05, t(15.02) = 0.34, p = 0.63, respectively). CONCLUSION: Although no significant differences were seen between sexes, small-to-moderate effect sizes and TOST analysis suggest male and female hemodynamic responses to LBNP are not equal following CYP450 inhibition. These data argue that CYP450 may have differential contributions to cerebral vascular control between the sexes and further exploration is warranted. 1. O’Brien MW, Kimmerly DS. Is “not different” enough to conclude similar cardiovascular responses across sexes? American Journal of Physiology-Heart and Circulatory Physiology 322: H355–H358, 2022. doi: 10.1152/ajpheart.00687.2021. 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.

Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein 1 (FABP1) and FABP1 Binding Alters Drug Metabolism.

Liver fatty acid binding protein 1 (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and homeostasis of endogenous lipids in the liver. Drugs have also been shown to bind to rat FABP1, but limited data are available for human FABP1 (hFABP1). FABP1 has a large binding pocket, and up to two fatty acids can bind to FABP1 simultaneously. We hypothesized that drug binding to hFABP1 results in formation of ternary complexes and that FABP1 binding alters drug metabolism. To test these hypotheses, native protein mass spectrometry (MS) and fluorescent 11-(dansylamino)undecanoic acid (DAUDA) displacement assays were used to characterize drug binding to hFABP1, and diclofenac oxidation by cytochrome P450 2C9 (CYP2C9) was studied in the presence and absence of hFABP1. DAUDA binding to hFABP1 involved high (Kd,1 = 0.2 μM) and low (Kd,2 > 10 μM) affinity binding sites. Nine drugs bound to hFABP1 with equilibrium dissociation constant (Kd) values ranging from 1 to 20 μM. None of the tested drugs completely displaced DAUDA from hFABP1, and fluorescence spectra showed evidence of ternary complex formation. Formation of DAUDA-hFABP1-diclofenac ternary complex was verified with native MS. Docking predicted diclofenac binding in the portal region of FABP1 with DAUDA in the binding cavity. The catalytic rate constant of diclofenac hydroxylation by CYP2C9 was decreased by ∼50% (P < 0.01) in the presence of FABP1. Together, these results suggest that drugs form ternary complexes with hFABP1 and that hFABP1 binding in the liver will alter drug metabolism and clearance. SIGNIFICANCE STATEMENT: Many commonly prescribed drugs bind fatty acid binding protein 1 (FABP1), forming ternary complexes with FABP1 and the fluorescent fatty acid 11-(dansylamino)undecanoic acid. These findings suggest that drugs will bind to apo-FABP1 and fatty acid-bound FABP1 in the human liver. The high expression of FABP1 in the liver, together with drug binding to FABP1, may alter drug disposition processes in vivo.

CYP2C9, CYP3A and CYP2C19 metabolize Δ9-tetrahydrocannabinol to multiple metabolites but metabolism is affected by human liver fatty acid binding protein (FABP1)

Δ9-tetrahydrocannabinol (THC) is the psychoactive constituent of cannabis. It is cleared predominantly via metabolism. Metabolism to 11-OH-THC by cytochrome P450 (CYP) 2C9 has been proposed as the main clearance pathway of THC, with the estimated fraction metabolized (fm) about 70%. The remaining clearance pathways are not well established, and it is unknown how THC is eliminated in individuals with reduced CYP2C9 activity. The goal of this study was to systematically identify the CYP enzymes contributing to THC clearance and characterize the metabolites formed. Further, this study aimed to characterize the impact of liver fatty acid binding protein (FABP1) on THC metabolism by human CYPs. THC was metabolized to at least four different metabolites including 11-OH-THC in human liver microsomes (HLMs) and with recombinant CYPs. 11-OH-THC was formed by recombinant CYP2C9 (Km,u = 0.77 nM, kcat = 12 min−1) and by recombinant CYP2C19 (Km,u = 2.2 nM, kcat = 14 min−1). The other three major metabolites were likely hydroxylations in the cyclohexenyl ring and were formed mainly by recombinant CYP3A4/5 (Km,u > 10 nM). HLM experiments confirmed the contributions of CYP2C9, CYP2C19 and CYP3A to THC metabolism. The presence of FABP1 and THC binding to FABP1 altered THC metabolism by recombinant CYPs and HLMs in an enzyme and metabolite specific manner. This suggests that FABP1 may interact with CYP enzymes and alter the fm by CYPs towards THC metabolism. In conclusion, this study is the first to systematically establish the metabolic profile of THC by human CYPs and characterize how FABP1 binding alters CYP mediated THC metabolism.

Correlation between Metabolic Parameters and Warfarin Dose in Patients with Heart Valve Replacement of Different Genotypes.

Warfarin has become the first choice for anticoagulation in patients who need lifelong anticoagulation due to its clinical efficacy and low price. However, the anticoagulant effect of warfarin is affected by many drugs, foods, etc. accompanied by a high risk of bleeding and embolism. The Vitamin K epoxide reductase complex 1 (VKORC1) and Cytochrome P450 2C9 (CYP2C9) genotypic variation can influence the therapeutic dose of warfarin. However, it is not clear whether there is a correlation between warfarin dose and liver function, kidney function and metabolic markers such as uric acid (UA) in patients with different genotypes. We performed a single-center retrospective cohort study to evaluate the factors affecting warfarin dose and to establish a dose conversion model for warfarin patients undergoing heart valve replacement. We studied 343 patients with a mechanical heart valve replacement, compared the doses of warfarin in patients with different warfarin-related genotypes (CYP2C9 and VKORC1), and analyzed the correlation between liver function, kidney function, UA and other metabolic markers and warfarin dose in patients with different genotypes following heart valve replacement. Genotype analysis showed that 72.01% of patients had CYP2C9*1/*1 and VKORC1 mutant AA genotypes. Univariate regression analysis revealed that the warfarin maintenance dose was significantly correlated with gender, age, body surface area (BSA), UA and genotype. There was no correlation with liver or kidney function. Multiple linear regression analysis showed that BSA, genotype and UA were the independent factors influencing warfarin dose. There is a significant correlation between UA content and warfarin dose in patients with heart valve replacement genotypes CYP2C9*1/*1/VKORC1(GA+GG), CYP2C9*1/*1/VKORC1AA and CYP2C9*1/*1/VKORC1AA.

Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP)2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

Relationship between CYP2C19 genotypes and proton pump inhibitorsʹs pharmacokinetics and pharmacodynamics: review

The purpose of this review is to provide clinicians with information and a concise interpretation of the results of pharmacogenetic testing for the cytochrome P450 2C19 (CYP2C19) genotype when choosing a proton pump inhibitor (PPI) dosage. PPIs are widely used for the treatment and prevention of common gastrointestinal diseases, including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, and other hypersecretory conditions. Most PPIs are metabolized predominantly by cytochrome P450 2C19 (CYP2C19) to form inactive metabolites, and the CYP2C19 genotype determines the action of PPIs, their efficacy and possible side effects. In clinical practice, a gastroenterologist or therapist is faced with problems of insufficient effectiveness or the development of adverse reactions when prescribing PPIs. Thus, consideration of CYP2C19 genotype appears to be necessary to determine the optimal PPI dosing regimen. The above served as a reason for generalizing in the presented review of literature data on the prescription of PPIs depending on the CYP2C19 genotype.

Evaluation of machine learning models for cytochrome P450 3A4, 2D6, and 2C9 inhibition.

Cytochrome P450 (CYP) enzymes are involved in the metabolism of approximately 75% of marketed drugs. Inhibition of the major drug-metabolizing P450s could alter drug metabolism and lead to undesirable drug-drug interactions. Therefore, it is of great significance to explore the inhibition of P450s in drug discovery. Currently, machine learning including deep learning algorithms has been widely used for constructing in silico models for the prediction of P450 inhibition. These models exhibited varying predictive performance depending on the use of machine learning algorithms and molecular representations. This leads to the difficulty in the selection of appropriate models for practical use. In this study, we systematically evaluated the conventional machine learning and deep learning models for three major P450 enzymes, CYP3A4, CYP2D6, and CYP2C9 from several perspectives, such as algorithms, molecular representation, and data partitioning strategies. Our results showed that the XGBoost and CatBoost algorithms coupled with the combined fingerprint/physicochemical descriptor features exhibited the best performance with Area Under Curve (AUC) of 0.92, while the deep learning models were generally inferior to the conventional machine learning models (average AUC reached 0.89) on the same test sets. We also found that data volume and sampling strategy had a minor effect on model performance. We anticipate that these results are helpful for the selection of molecular representations and machine learning/deep learning algorithms in the P450 model construction and the future model development of P450 inhibition.

Modeled Hepatic/Plasma Exposures of Fluvastatin Prescribed Alone in Subjects with Impaired Cytochrome P450 2C9*3 as One of Possible Determinant Factors Likely Associated with Hepatic Toxicity Reported in a Japanese Adverse Event Database.

Fluvastatin is a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor that competitively inhibits human cytochrome P450 (P450) 2C9 in vitro. Drug interactions between a variety of P450 2C9 substrates/inhibitors and fluvastatin can increase the incidence of fluvastatin-related hepatic or skeletal muscle toxicity in vivo. In this survey, the prescribed dosage of fluvastatin was reduced or discontinued in 133 of 164 patients receiving fluvastatin alone, as recorded in the Japanese Adverse Drug Event Report database of spontaneously reported events. The median days to onset of fluvastatin-related disorders were in the range 30-35 d in the 87 patients. Therefore, we aimed to focus on fluvastatin and, using the pharmacokinetic modeling technique, estimated the virtual plasma and hepatic exposures in subjects harboring the impaired CYP2C9*3 allele. The plasma concentrations of fluvastatin modeled after a virtual oral 20-mg dose increased in homozygotes with CYP2C9*3; the area under the plasma concentration curve was 4.9-fold higher than that in Japanese homozygotes for wild-type CYP2C9*1. The modeled hepatic concentrations of fluvastatin in patients with CYP2C9*3/*3 after virtual daily 20-mg doses for 7 d were 31-fold higher than those in subjects with CYP2C9*1/*1. However, heterozygous Chinese patients with CYP2C9*1/*3 reportedly have a limited elevation (1.2-fold) in plasma maximum concentrations. Virtual hepatic/plasma exposures in subjects harboring the impaired CYP2C9*3 allele estimated using pharmacokinetic modeling indicate that such exposure could be a causal factor for hepatic disorders induced by fluvastatin prescribed alone in a manner similar to that for interactions with a variety of co-administered drugs.