Decreased plasma exposure of clopidogrel active metabolite in rats after long-term treatment with clopidogrel.

Clopidogrel (Clop) is oxidized by cytochrome P450s (CYPs) to an active thiol metabolite, Clop-AM, to inhibit platelet activation and aggregation. As an irreversible inhibitor of CYP2B6 and CYP2C19, clopidogrel may inhibit its own metabolism after long-term administration. The study compared the pharmacokinetic profiles of clopidogrel and its metabolites in rats receiving a single or a 2 week administration of Clop. The mRNA and protein levels of hepatic clopidogrel-metabolizing enzymes and their enzymatic activities were analyzed to explore their contribution to any altered plasma exposure of Clop and its metabolites. The results showed that long-term treatment with clopidogrel significantly decreased the AUC(0-t) and Cmax values of Clop-AM in rats, accompanied with markedly impaired catalytic activities of Clop-metabolizing CYPs including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4. It suggests that consecutive administration of Clop to rats decreases hepatic CYPs activities, which may, in turn, inhibit clopidogrel metabolism and then reduce Clop-AM plasma exposure. Therefore, long-term treatment with clopidogrel has the potential to reduce its anti-platelet activity and to increase the risk of drug-drug interaction.

Effect of chronic unpredicted mild stress-induced depression on clopidogrel pharmacokinetics in rats.

Background: Clopidogrel is widely used to prevent and treat cardiovascular atherosclerosis and thrombosis. However, disturbance in the expression and activity of liver cytochrome metabolic enzymes significantly changes clopidogrel efficacy. Therefore, the effect of chronic unpredictable mild stress (CUMS)-induced depression on the expression of liver cytochrome metabolic enzymes and clopidogrel pharmacokinetics in rats were explored. Methods: Nine different CUMSs were selected to establish a rat model of depression. Open field experiment and sucrose preference test were applied to explore the depressive behaviors. The concentration of serotonin in the cortex of depressed rats was determined using enzyme linked immunosorbent assay (ELISA). All rats were given 10 mg/kg clopidogrel orally after 12 weeks, and blood samples were collected at different time points. The clopidogrel concentration and CYP2C19/ CYP2C9 activity in rat liver microsomes were assayed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The rat liver drug enzymes expression was determined by Real-Time Quantitative Reverse Transcription PCR (RT-qPCR). Results: Open field experiment and sucrose preference test indicated the successful construction of the CUMS-induced depression model. The concentration of serotonin in the cortex of depressed rats decreased by 42.56% (∗∗ p < 0.01). The area under the curve of clopidogrel pharmacokinetics decreased by 33.13% (∗ p < 0.05) in the depression rats, while distribution volume and clearance increased significantly (∗∗ p < 0.01). The half-time and distribution volume did not significantly differ. The CYP2C19 and CYP2C9 activity of liver microsomes in the CUMS-induced depression group were significantly higher than that in the control group (∗∗ p < 0.01). CYP2C11 and CYP1A2 mRNA expression up-regulated approximately 1.3 - fold in the depressed rat livers compared with that in the control, whereas that of CYP2C13 was down-regulated by 27.43% (∗∗ p < 0.01). CYP3A1 and CYP2C12 expression were slightly up-regulated, and that of CES1 did not change. Conclusions: These results indicated that CUMS-induced depression altered clopidogrel pharmacokinetics, and the change in CYP450 activity and expression in depressed rat livers might contribute to the disturbance of clopidogrel pharmacokinetics.

Dosage optimization of clopidogrel via a precision medicine approach: the way forward.

Clopidogrel is a prodrug chiefly metabolized by the hepatic isoenzyme CYP2C19 to its active metabolite that inhibits the platelet aggregation. It has been proven in many populations that the genetic polymorphism of CYP2C19 has influence on the pharmacokinetic and or pharmacodynamics of this drug and resulting in high inter-individual variability in the treatment outcomes. As CYP2C19 genetic polymorphism is highly prevalent among the Asian population, the influence of the same on the pharmacokinetics and; thereby, the pharmacodynamics of clopidogrel needs more attention. Using the pharmacogenetic information for drug therapy could help overcome these issues and to optimize the dosage regimen of clopidogrel, this review advocates the precision medicine approach for reducing the clopidogrel resistance and adverse cardiovascular events.

Effects of the CYP2C19 LoF allele on major adverse cardiovascular events associated with clopidogrel in acute coronary syndrome patients undergoing percutaneous coronary intervention: a meta-analysis.

The aggregated risk of major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS) patients inheriting CYP2C19 loss-of function (LoF) alleles who underwent percutaneous coronary intervention (PCI) and were treated with clopidogrel is controversial. In the current study, we searched the literature in different databases for eligible studies. The risk ratio (RR) was measured where p<0.05 was statistically significant. The ACS patients with either one or two CYP2C19 LoF alleles who underwent PCI, treated with clopidogrel were correlated with a significantly escalated risk of MACE compared with noncarriers (RR: 1.53, 95% CI: 1.39-1.69, p < 0.00001), driven by CV death (RR: 1.88, 95% CI: 1.18-3.01, p = 0.008), MI (RR: 1.67, 95% CI: 1.21-2.31, p = 0.002) and ST (RR: 1.90, 95% CI: 1.27-2.84, p = 0.002). Patients with two CYP2C19 LoF alleles were correlated with significantly greater risk of MACE compared with noncarriers (RR: 3.91, 95% CI: 2.78-5.50, p < 0.00001). Further analysis revealed that the risk of MACE was markedly significant in Asian patients (RR: 2.02, 95% CI: 1.67-2.44, p < 0.00001) and was comparatively low significance in western patients (RR: 1.35, 95% CI: 1.20-1.52, p < 0.00001). There was no significantly different bleeding events in patients with CYP2C19 LoF alleles compared with noncarriers (RR: 0.99, 95% CI: 0.85-1.15, p = 0.87). The ACS patients inheriting CYP2C19 LoF alleles, who underwent PCI and were treated with clopidogrel were correlated with significantly increased risk of MACE compared with noncarriers.

Clopidogrel-herb Interactions: A Pharmacokinetic and Pharmacodynamic Assessment in a Rat Model.

BACKGROUND: Herbs usually contain a mixture of biologically active constituents, which can interact with numerous prescribed drugs and alter their safety profiles. OBJECTIVES: The current investigation was aimed to evaluate the effect of commonly used herbal products including black seed (Nigella sativa), garden cress (Lepidium sativum), and fenugreek (Trigonella foenum-graecum) on the pharmacokinetics and pharmacodynamics of clopidogrel using a Wistar rat model. METHODS: A GC-MS analysis revealed the presence of several phytoconstitutents (polyphenols) in the extracts of black seed, garden cress, and fenugreek. These polyphenols have the potential to interfere with clopidogrel effect. Plasma concentrations of clopidogrel were measured at different time points in the absence and presence of the concurrent use of tested herbal products and the pharmacokinetic parameters were calculated. Bleeding time was measured in various groups as a measure of the antiplatelet effect of clopidogrel. RESULTS: Area under the plasma concentration-time curves (AUC0-∞) of clopidogrel were 35.53 ±0.89 µg/ml*h (p<0.05), 26.01 ±0.90 µg/ml*h (p>0.05) and 32.80 ±2.51 µg/ml*h (p<0.05) in the black seed, garden cress and fenugreek group, respectively, compared with that of the control group (27.02 ±0.42 µg/ml*h). Treatment with black seed also caused an increase in clopidogrel Cmax by 31.52% (p<0.05) and with fenugreek by 21.42% (p<0.05); Cmax, did not changed with garden cress treatment (6.48 ±0.15 µg/ml versus 6.12 ±0.21 µg/ml, p>0.05). The pharmacodynamic evaluation of the antiplatelet effect of clopidogrel in the presence of herbal products treatment showed a significant prolongation in the bleeding time from a control baseline by ~22-26%, and by added ~8-12% in reference to clopidogrel therapeutic effect (p<0.05). CONCLUSION: The concurrent use of black seed, fenugreek, or garden cress can alter the pharmacokinetics and pharmacodynamics of clopidogrel to varying degrees due to the presence of various bioactive polyphenols. This is probably due to changes in drug disposition and its antiplatelet action. Further confirmation can determine the clinical relevance of these observations and identify the exact constituents responsible for such activities.

Evaluation of the effect of carrier material on modification of release characteristics of poor water soluble drug from liquisolid compacts.

Liquisolid compact is a novel dosage form in which a liquid medication (liquid drug, drug solution/dispersion in non-volatile solvent/solvent system) is converted to a dry, free flowing powder and compressed. Objective of the study was to elucidate the effect of carrier material on release characteristics of clopidogrel from liquisolid compacts. Different formulations of liquisolid compacts were developed using microcrystalline cellulose, starch maize, polyvinyl pyrollidone and hydroxypropyl methylcellulose as carrier material in three concentrations (40, 30 and 20%, w/w). Liquid vehicle was selected on the basis of solubility of clopidogrel. Colloidal silicondioxide was used as coating material and ratio of carrier to coating material was kept 10. A control formulation comprised of microcrystalline cellulose (diluents), tabletose-80 (diluents), primojel (disintegrant) and magnesium stearate (lubricant) was prepared by direct compression technique and was used for comparison. All the formulations were evaluated at pre and post compression level. Acid solubility profile showed higher solubility in HCl buffer pH2 (296.89±3.49 µg/mL). Mixture of propylene glycol and water (2:1, v/v) was selected as liquid vehicle. Drug content was in the range of 99-101% of the claimed quantity. All the formulations showed better mechanical strength and their friability was within the official limits (<1%). Microcrystalline cellulose and starch maize resulted in faster drug release while polyvinyl pyrollidone and HPMC resulted in sustaining drug release by gel formation. It is concluded from results that both fast release and sustained release of clopidogrel can be achieved by proper selection of carrier material.

Pharmacokinetic/pharmacodynamic modeling of drug interactions at the P2Y12 receptor between selatogrel and oral P2Y12 antagonists.

Selatogrel is a potent and reversible P2Y12 receptor antagonist developed for subcutaneous self-administration by patients with suspected acute myocardial infarction. After single-dose emergency treatment with selatogrel, patients are switched to long-term treatment with oral P2Y12 receptor antagonists. Selatogrel shows rapid onset and offset of inhibition of platelet aggregation (IPA) to overcome the critical initial time after acute myocardial infarction. Long-term benefit is provided by oral P2Y12 receptor antagonists such as clopidogrel, prasugrel, and ticagrelor. A population pharmacokinetic (PK)/pharmacodynamic (PD) model based on data from 545 subjects in 4 phase I and 2 phase II studies well described the effect of selatogrel on IPA alone and in combination with clopidogrel, prasugrel, and ticagrelor. The PK of selatogrel were described by a three-compartment model. The PD model included a receptor-pool compartment to which all drugs can bind concurrently, reversibly or irreversibly, depending on their mode of action. Furthermore, ticagrelor and its active metabolite can bind to the selatogrel-receptor complex allosterically, releasing selatogrel from the binding site. The model provided a framework for predicting the effect on IPA of selatogrel followed by reversibly and irreversibly binding oral P2Y12 receptor antagonists for sustained effects. Determining the timepoint for switching from emergency to maintenance treatment is critical to achieve sufficient IPA at all times. Simulations based on the interaction model showed that loading doses of clopidogrel and prasugrel administered 15 h and 4.5 h after selatogrel, respectively, provide sustained IPA with clinically negligible drug interaction. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Selatogrel is a potent reversible P2Y12 receptor antagonist developed for subcutaneous self-administration by patients in case of suspected acute myocardial infarction. Transition to oral P2Y12 receptor antagonists without drug interaction and sufficient inhibition of platelet aggregation must be assured at all times. WHAT QUESTION DID THIS STUDY ADDRESS? The pharmacokinetic/pharmacodynamic model semimechanistically describes the effect of selatogrel on platelet inhibition alone and in combination with the oral P2Y12 receptor antagonists clopidogrel, prasugrel, and ticagrelor. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Model-based simulations showed that loading doses of clopidogrel and prasugrel can be administered from 15 h and 4.5 h after selatogrel, respectively. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? These results support guiding the clinical transition from selatogrel emergency treatment to oral maintenance therapy in a safe and efficacious way.

Correlation study of CYP2C19 gene polymorphism and clopidogrel resistance in Han Chinese patients with cerebral infarction in Guizhou region.

ABSTRACT: This study conducts a correlation exploration of CYP2C19 gene polymorphism and clopidogrel resistance in Han Chinese patients with cerebral infarction in Guizhou Region.A total of 270 Han Chinese patients with cerebral infarction, who were hospitalized in our hospital from January 2016 to January 2018, are selected. These patients were divided into 2 groups, clopidogrel resistance group (n = 60) and clopidogrel sensitive group (n = 210). According to the TEG results, the CYP2C19 gene polymorphism detection was carried out by using the PCR-RFLP method, while IL-6 level in the patient's blood was measured by using the ELISA method.The resistance group occupies 22.22%. The platelet inhibition ratio of the resistance group was 23 ±â€Š7%, which was significantly lower than that of the sensitive group (65 ±â€Š13%), and the difference was statistically significant (P < .05). The Logisitic regression analysis revealed that the history of diabetes, history of high blood pressure, increase in low density lipoprotein and CYP2C19 mutant gene were independent risk factors of clopidogrel resistance. After treatment, the serum IL-6 level of patients in the resistance group was 17.21 ±â€Š0.98 ng/L, which was significant higher than that of patients in the sensitive group (11.21 ±â€Š0.68 ng/L), and the difference was statistically significant (P < .05).Patients with cerebral infarction in Guizhou region have a higher occurrence rate of clopidogrel resistance. Clopidogrel resistance not only will weaken the anti-inflammatory action of the drug, but also correlates with the patient's CYP2C19 mutant gene and blood lipid level.

Next-Generation Sequencing of CYP2C19 in Stent Thrombosis: Implications for Clopidogrel Pharmacogenomics.

PURPOSE: Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies. METHODS: Seventy ST cases on clopidogrel identified from the PLATO trial (n = 58) and Mayo Clinic biorepository (n = 12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations. RESULTS: Poor metabolizers (n = 4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n = 29) than controls (n = 18). Functional studies of CYP2C19 exonic variants (n = 11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n = 169) compared with controls (n = 84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases. CONCLUSION: NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.

Implementation and management outcomes of pharmacogenetic CYP2C19 testing for clopidogrel therapy in clinical practice.

PURPOSE: The antiplatelet prodrug clopidogrel is bioactivated by the polymorphic enzyme CYP2C19. Prospective clinical studies demonstrated an association between CYP2C19 loss of function (LoF) variants and an increased risk of thrombotic events under clopidogrel, but pharmacogenetic (PGx) testing is not frequently implemented in clinical practice. We report our experience with PGx-guided clopidogrel therapy with particular regard to clinically relevant patient management changes. METHODS: We conducted an observational study analyzing patients that underwent PGx testing for clopidogrel therapy at two Swiss hospitals. Primary outcome was the proportion of patients with clinically relevant PGx-based management recommendations and their implementation. The association of recurrent ischemic events under clopidogrel with CYP2C19 LoF variants and other factors was explored in a multivariate case-control analysis. RESULTS: Among 56 patients undergoing PGx testing, 18 (32.1%) were classified as CYP2C19 intermediate or poor metabolizers. This resulted in 17 recommendations for a change of antiplatelet therapy, which were implemented in 12 patients (70.1%). In the remaining five patients, specific reasons for non-implementation could be identified. Recurrent ischemic events under clopidogrel were associated with LoF variants (OR 2.2, 95% CI 0.3-14.4) and several cardiovascular risk factors. Associations were not statistically significant in our small study, but plausible and in line with estimates from large prospective studies. CONCLUSION: PGx-guided clopidogrel therapy can identify patients with an elevated risk of ischemic events and offer evidence-based alternative treatments. Successful implementation in clinical practice requires a personalized interdisciplinary service that evaluates indications and additional risk factors, provides specific recommendations, and proactively follows their implementation.

Impact of selected genetic factors on clopidogrel inactive metabolite level and antiplatelet response in patients after percutaneous coronary intervention.

BACKGROUND AND OBJECTIVE: Clopidogrel is frequently used as part of optimal dual antiplatelet therapy in high-bleeding risk patients with the acute coronary syndrome. The concentration of the inactive carboxylic acid metabolite of clopidogrel might be useful to evaluate the response to clopidogrel therapy. Therefore, we sought to correlate the inhibition of platelet aggregation with the plasma level of the inactive metabolite of clopidogrel in patients after percutaneous coronary interventions (PCI) and their associations with the most frequently studied genetic polymorphisms. For this purpose, the fast and simple HPLC method for determining the concentration of the inactive metabolite was developed. METHODS: The effect of CYP2C19, CYP3A4/5, ABCB1 and PON1 genes on the plasma inactive metabolite concentration of clopidogrel and the platelet aggregation was investigated in 155 patients before and after PCI. RESULTS: The concentration of the inactive metabolite of clopidogrel was not significantly different in the intermediate metabolizers (IM) of CYP2C19 compared with extensive metabolizers (EM) both before and after PCI, while inhibition of platelet aggregation was found to be significantly better in EM than in IM. The presence of the A allele at position 2677 in the ABCB1 gene was associated with a significantly lower concentration of inactive metabolite of clopidogrel before PCI. CONCLUSION: The CYP2C19*2 allele was associated with decreased platelet reactivity during clopidogrel therapy before and after PCI. Simultaneous determination of platelet aggregation and concentration of the inactive clopidogrel metabolite may be useful in clinical practice to find the cause of adverse effects or insufficient treatment effect in patients chronically treated with clopidogrel.

MirSNPs in clopidogrel metabolism genes predict cardiovascular disease risk: a case-control study and meta-analysis.

Aim: The present study was conducted to decipher the inter-relationship of SNPs and miRNAs involved in pharmacogenomics of clopidogrel on predisposition to cardiovascular diseases (CVDs). Materials & methods: A case-control study was conducted on 410 cases and 386 controls to analyze the association of 13 mirSNPs on CVDs risk. Genotyping was performed by tetra-primer amplification refractory mutation system PCR and validated using Sanger DNA sequencing. miRNA expression analysis was performed using TaqMan assays. A meta-analysis was performed for PON1 rs662 with coronary artery disease. Results & conclusion:PON1 rs662, PON1 rs3917577, CYP3A5 rs15524, COL4A1 rs874204 and PTGIR rs1126510 polymorphisms showed association with CVDs. The miRNA hsa-miR-224-5p showed differential expression in the PON1 rs3917577 GG genotype. The meta-analysis showed the population-specific impact of PON1 rs662 on South Asian and Middle East populations.

Investigation of the interaction between proton pump inhibitors and clopidogrel using VerifyNow P2Y12 assay.

BACKGROUND: Randomized trials and observation studies have revealed conflicting results regarding the interaction between clopidogrel and proton pump inhibitors (PPIs). The aim of our study was to provide laboratory evidence regarding whether PPIs blunt the antiplatelet reactivity of clopidogrel. METHODS: We included records of Asian patients who received clopidogrel treatment for cardiovascular or cerebrovascular events and the VerifyNow P2Y12 assay for platelet reactivity monitoring. The responsiveness of antiplatelet effect to clopidogrel was analyzed according to 3 criteria:Results: Patients treated without PPIs did not differ significantly from those concomitantly treated with PPIs in terms of levels of PI (25.7% ± 24.3% vs 23.0 ± 25.3%, P = .4315), PRU (187.3 ± 74.0 vs 197.4 ±â€Š77.3, P = .3373), or responsiveness to antiplatelet (adjusted absolute risk, 3.5%; 95% confidence interval, - 10.7 to 17.7%; P = .6297). Patients treated with lansoprazole, esomeprazole, pantoprazole, and rabeprazole exhibited no significant differences in PRU or PI levels compared with those treated without PPIs. By contrast, patients treated with dexlansoprazole exhibited a significantly decreased level of PI (25.7% ±â€Š24.3% vs 14.0% ±â€Š21.6%, P = .0297) and responsiveness to clopidogrel under the criterion PI > 20% (adjusted absolute risk: 10.5%; 95% confidence interval: 2.6% to 43.6%; P = .0274). CONCLUSION: No robust interaction between clopidogrel and PPIs was found, but caution should be exercised in the concomitant use of dexlansoprazole and clopidogrel in Asians.

Pharmacokinetic, pharmacodynamic, and pharmacogenetic assays to monitor clopidogrel therapy.

Clopidogrel is the most common and widely used antiplatelet agent for patients with coronary artery disease following confirmation by electrocardiographic studies. The nonresponsiveness of patients to clopidogrel and the possibility of testing for clopidogrel resistance by platelet function assays (PFA) are contentious issues. Light transmission aggregometry (LTA) is considered as the gold standard test among all PFA. In this review, the most commonly used PFA used for monitoring the effect of clopidogrel, LTA, vasodilator-stimulated phosphoprotein assay phosphorylation, rotational thromboelastometry (ROTEM) delta and ROTEM platelet, thromboelastography, PFA-100, VerifyNow P2Y12 assay, Multiplate analyzer, Plateletworks assay and pharmacogenetic studies, are comparatively discussed including their principles of action, advantages, and disadvantages. VerifyNow P2Y12 assay can be accepted as the ideal point of care test out of the discussed assays. However, modified assays are required which could overcome the limitations associated with currently available assays.

Pharmacogenomics for Primary Care: An Overview.

Most of the prescribing and dispensing of medicines happens in primary care. Pharmacogenomics (PGx) is the study and clinical application of the role of genetic variation on drug response. Mounting evidence suggests PGx can improve the safety and/or efficacy of several medications commonly prescribed in primary care. However, implementation of PGx has generally been limited to a relatively few academic hospital centres, with little adoption in primary care. Despite this, many primary healthcare providers are optimistic about the role of PGx in their future practice. The increasing prevalence of direct-to-consumer genetic testing and primary care PGx studies herald the plausible gradual introduction of PGx into primary care and highlight the changes needed for optimal translation. In this article, the potential utility of PGx in primary care will be explored and on-going barriers to implementation discussed. The evidence base of several drug-gene pairs relevant to primary care will be outlined with a focus on antidepressants, codeine and tramadol, statins, clopidogrel, warfarin, metoprolol and allopurinol. This review is intended to provide both a general introduction to PGx with a more in-depth overview of elements relevant to primary care.

Exploring pharmacogenetic difference using adverse event database: an example of clopidogrel and cardiovascular events.

Background: Poor clopidogrel metabolizers, carrying a cytochrome P450 2C19 loss-of-function allele, are more frequent among East Asians than Caucasians/White. Materials & methods: The Korea adverse event reporting system database and a case/noncase study design were used to examine the disproportionality of cardiovascular events following clopidogrel use. The US FDA's adverse event reporting system database was also analyzed for comparison. Results: In the Korea adverse event reporting system data, the clopidogrel reporting odds ratio for cardiovascular events was 7.34, more than double that of ticagrelor. In the FDA's adverse event reporting system data, the clopidogrel reporting odds ratio was 4.69, lower than that of ticagrelor. Adjustment for covariates did not change the trend. Conclusion: Considering the prevalence of poor clopidogrel metabolizers and the reported cardiovascular events among Koreans, rigorous clinical management is required for clopidogrel users.

Modelled plasma concentrations of pemafibrate with co-administered typical cytochrome P450 inhibitors clopidogrel, fluconazole or clarithromycin predicted by physiologically based pharmacokinetic modelling in virtual populations.

Oral antidyslipidaemic drug pemafibrate is cleared from human plasma via hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 and oxidation by cytochromes P450 (P450) 2C8, 2C9 and 3A4. The pharmacokinetic profiles of pemafibrate with virtual administrations of P450 inhibitors and/or disease interactions were generated using a physiologically based pharmacokinetic (PBPK) model previously established for co-administration of pemafibrate with OATP1B1 inhibitors. This PBPK model was validated in the current study using reported maximum pemafibrate plasma concentrations and areas under the curve from interaction studies in healthy subjects co-administered with clopidogrel (P450 2C8 inhibitor), fluconazole (P450 2C9/3A4 inhibitor) or clarithromycin (P450 3A4 inhibitor). Virtual co-administrations of pemafibrate with clopidogrel, fluconazole or clarithromycin increased the predicted plasma exposures of pemafibrate 1.4-1.7-fold, 1.2-1.4-fold and 2.9-11-fold, respectively, in subjects with or without moderate or severe renal impairment or Child-Pugh A or B liver cirrhosis. Some of the exposure-enhancing effects of clarithromycin may originate from its inhibitory potential toward OATP1B1, because the estimated effects of itraconazole (a P450 3A4 inhibitor) were only minor. Simulations using the current PBPK model in groups of virtual subjects with or without renal or hepatic impairment revealed modified pharmacokinetic profiles for pemafibrate following co-administration of typical P450 inhibitors.

Natural Products as Modulators of CES1 Activity.

Carboxylesterase (CES) 1 is the predominant esterase expressed in the human liver and is capable of catalyzing the hydrolysis of a wide range of therapeutic agents, toxins, and endogenous compounds. Accumulating studies have demonstrated associations between the expression and activity of CES1 and the pharmacokinetics and/or pharmacodynamics of CES1 substrate medications (e.g., methylphenidate, clopidogrel, oseltamivir). Therefore, any perturbation of CES1 by coingested xenobiotics could potentially compromise treatment. Natural products are known to alter drug disposition by modulating cytochrome P450 and UDP-glucuronosyltransferase enzymes, but this issue is less thoroughly explored with CES1. We report the results of a systematic literature search and discuss natural products as potential modulators of CES1 activity. The majority of research reports reviewed were in vitro investigations that require further confirmation through clinical study. Cannabis products (Δ 9-tetrahydrocannabinol, cannabidiol, cannabinol); supplements from various plant sources containing naringenin, quercetin, luteolin, oleanolic acid, and asiatic acid; and certain traditional medicines (danshen and zhizhuwan) appear to pose the highest inhibition potential. In addition, ursolic acid, gambogic acid, and glycyrrhetic acid, if delivered intravenously, may attain high enough systemic concentrations to significantly inhibit CES1. The provision of a translational interpretation of in vitro assessments of natural product actions and interactions is limited by the dearth of basic pharmacokinetic data of the natural compounds exhibiting potent in vitro influences on CES1 activity. This is a major impediment to assigning even potential clinical significance. The modulatory effects on CES1 expression after chronic exposure to natural products warrants further investigation. SIGNIFICANCE STATEMENT: Modulation of CES1 activity by natural products may alter the course of treatment and clinical outcome. In this review, we have summarized the natural products that can potentially interact with CES1 substrate medications. We have also noted the limitations of existing reports and outlined challenges and future directions in this field.