Unraveling the Effects of Acute Inflammation on Pharmacokinetics: A Model-Based Analysis Focusing on Renal Glomerular Filtration Rate and Cytochrome P450 3A4-Mediated Metabolism

Background and Objectives Acute inflammation caused by infections or sepsis can impact pharmacokinetics. We used a model-based analysis to evaluate the effect of acute inflammation as represented by interleukin-6 (IL-6) levels on drug clearance, focusing on renal glomerular filtration rate (GFR) and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. Methods A physiologically based model incorporating renal and hepatic drug clearance was implemented. Functions correlating IL-6 levels with GFR and in vitro CYP3A4 activity were derived and incorporated into the modeling framework. We then simulated treatment scenarios for hypothetical drugs by varying the IL-6 levels, the contribution of renal and hepatic drug clearance, and protein binding. The relative change in observed area under the concentration-time curve (AUC) was computed for these scenarios. Results Inflammation showed opposite effects on drug exposure for drugs eliminated via the liver and kidney, with the effect of inflammation being inversely proportional to the extraction ratio (ER). For renally cleared drugs, the relative decrease in AUC was close to 30% during severe inflammation. For CYP3A4 substrates, the relative increase in AUC could exceed 50% for low-ER drugs. Finally, the impact of inflammation-induced changes in drug clearance is smaller for drugs with a larger unbound fraction. Conclusion This analysis demonstrates differences in the impact of inflammation on drug clearance for different drug types. The effects of inflammation status on pharmacokinetics may explain the inter-individual variability in pharmacokinetics in critically ill patients. The proposed model-based analysis may be used to further evaluate the effect of inflammation, i.e., by incorporating the effect of inflammation on other drug-metabolizing enzymes or physiological processes

The impact of CYP2C19 genotype on phenoconversion by concomitant medication

Introduction: Pharmacogenetics-informed drug prescribing is increasingly applied in clinical practice. Typically, drug metabolizing phenotypes are determined based on genetic test results, whereupon dosage or drugs are adjusted. Drug-drug-interactions (DDIs) caused by concomitant medication can however cause mismatches between predicted and observed phenotypes (phenoconversion). Here we investigated the impact of CYP2C19 genotype on the outcome of CYP2C19-dependent DDIs in human liver microsomes.Methods: Liver samples from 40 patients were included, and genotyped for CYP2C19*2, *3 and *17 variants. S-mephenytoin metabolism in microsomal fractions was used as proxy for CYP2C19 activity, and concordance between genotype-predicted and observed CYP2C19 phenotype was examined. Individual microsomes were subsequently co-exposed to fluvoxamine, voriconazole, omeprazole or pantoprazole to simulate DDIs.Results: Maximal CYP2C19 activity (Vmax) in genotype-predicted intermediate metabolizers (IMs; *1/*2 or *2/*17), rapid metabolizers (RMs; *1/*17) and ultrarapid metabolizers (UMs; *17/*17) was not different from Vmax of predicted normal metabolizers (NMs; *1/*1). Conversely, CYP2C19*2/*2 genotyped-donors exhibited Vmax rates ∼9% of NMs, confirming the genotype-predicted poor metabolizer (PM) phenotype. Categorizing CYP2C19 activity, we found a 40% concordance between genetically-predicted CYP2C19 phenotypes and measured phenotypes, indicating substantial phenoconversion. Eight patients (20%) exhibited CYP2C19 IM/PM phenotypes that were not predicted by their CYP2C19 genotype, of which six could be linked to the presence of diabetes or liver disease. In subsequent DDI experiments, CYP2C19 activity was inhibited by omeprazole (−37% ± 8%), voriconazole (−59% ± 4%) and fluvoxamine (−85% ± 2%), but not by pantoprazole (−2 ± 4%). The strength of CYP2C19 inhibitors remained unaffected by CYP2C19 genotype, as similar percental declines in CYP2C19 activity and comparable metabolism-dependent inhibitory constants (Kinact/KI) of omeprazole were observed between CYP2C19 genotypes. However, the consequences of CYP2C19 inhibitor-mediated phenoconversion were different between CYP2C19 genotypes. In example, voriconazole converted 50% of *1/*1 donors to a IM/PM phenotype, but only 14% of *1/*17 donors. Fluvoxamine converted all donors to phenotypic IMs/PMs, but *1/*17 (14%) were less likely to become PMs than *1/*1 (50%) or *1/*2 and *2/*17 (57%).Conclusion: This study suggests that the differential outcome of CYP2C19-mediated DDIs between genotypes are primarily dictated by basal CYP2C19 activity, that may in part be predicted by CYP2C19 genotype but likely also depends on disease-related factors

PRMT3 inhibitor SGC707 reduces triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice

Protein arginine methyltransferase 3 (PRMT3) is a co-activator of liver X receptor capable of selectively modulating hepatic triglyceride synthesis. Here we investigated whether pharmacological PRMT3 inhibition can diminish the hepatic steatosis extent and lower plasma lipid levels and atherosclerosis susceptibility. Hereto, male hyperlipidemic low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet and injected 3 times per week intraperitoneally with PRMT3 inhibitor SGC707 or solvent control. Three weeks into the study, SGC707-treated mice developed severe pruritus and scratching-associated skin lesions, leading to early study termination. SGC707-treated mice exhibited 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. Atherosclerotic lesions were virtually absent in all experimental mice. Plasma metabolite analysis revealed that levels of taurine-conjugated bile acids were ~ threefold increased (P < 0.001) in response to SGC707 treatment, which was paralleled by systemically higher bile acid receptor TGR5 signalling. In conclusion, we have shown that SGC707 treatment reduces hepatic steatosis and plasma triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. These findings suggest that pharmacological PRMT3 inhibition can serve as therapeutic approach to treat non-alcoholic fatty liver disease and dyslipidemia/atherosclerosis, when unwanted effects on cholesterol and bile acid metabolism can be effectively tackled

PRMT3 inhibitor SGC707 reduces triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice

Protein arginine methyltransferase 3 (PRMT3) is a co-activator of liver X receptor capable of selectively modulating hepatic triglyceride synthesis. Here we investigated whether pharmacological PRMT3 inhibition can diminish the hepatic steatosis extent and lower plasma lipid levels and atherosclerosis susceptibility. Hereto, male hyperlipidemic low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet and injected 3 times per week intraperitoneally with PRMT3 inhibitor SGC707 or solvent control. Three weeks into the study, SGC707-treated mice developed severe pruritus and scratching-associated skin lesions, leading to early study termination. SGC707-treated mice exhibited 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. Atherosclerotic lesions were virtually absent in all experimental mice. Plasma metabolite analysis revealed that levels of taurine-conjugated bile acids were ~ threefold increased (P < 0.001) in response to SGC707 treatment, which was paralleled by systemically higher bile acid receptor TGR5 signalling. In conclusion, we have shown that SGC707 treatment reduces hepatic steatosis and plasma triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. These findings suggest that pharmacological PRMT3 inhibition can serve as therapeutic approach to treat non-alcoholic fatty liver disease and dyslipidemia/atherosclerosis, when unwanted effects on cholesterol and bile acid metabolism can be effectively tackled.Analytical BioScience

The effect of a comprehensive lifestyle intervention on cardiovascular risk factors in pharmacologically treated patients with stable cardiovascular disease compared to usual care: a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>The additional benefit of lifestyle interventions in patients receiving cardioprotective drug treatment to improve cardiovascular risk profile is not fully established.</p> <p>The objective was to evaluate the effectiveness of a target-driven multidisciplinary structured lifestyle intervention programme of 6 months duration aimed at maximum reduction of cardiovascular risk factors in patients with cardiovascular disease (CVD) compared with usual care.</p> <p>Methods</p> <p>A single centre, two arm, parallel group randomised controlled trial was performed. Patients with stable established CVD and at least one lifestyle-related risk factor were recruited from the vascular and cardiology outpatient departments of the university hospital. Blocked randomisation was used to allocate patients to the intervention (n = 71) or control group (n = 75) using an on-site computer system combined with allocations in computer-generated tables of random numbers kept in a locked computer file. The intervention group received the comprehensive lifestyle intervention offered in a specialised outpatient clinic in addition to usual care. The control group continued to receive usual care. Outcome measures were the lifestyle-related cardiovascular risk factors: smoking, physical activity, physical fitness, diet, blood pressure, plasma total/HDL/LDL cholesterol concentrations, BMI, waist circumference, and changes in medication.</p> <p>Results</p> <p>The intervention led to increased physical activity/fitness levels and an improved cardiovascular risk factor profile (reduced BMI and waist circumference). In this setting, cardiovascular risk management for blood pressure and lipid levels by prophylactic treatment for CVD in usual care was already close to optimal as reflected in baseline levels. There was no significant improvement in any other risk factor.</p> <p>Conclusions</p> <p>Even in CVD patients receiving good clinical care and using cardioprotective drug treatment, a comprehensive lifestyle intervention had a beneficial effect on some cardiovascular risk factors. In the present era of cardiovascular therapy and with the increasing numbers of overweight and physically inactive patients, this study confirms the importance of risk factor control through lifestyle modification as a supplement to more intensified drug treatment in patients with CVD.</p> <p>Trial registration</p> <p>ISRCTN69776211 at <url>http://www.controlled-trials.com</url></p

Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle.

Taste-sensing type 2 receptors (TAS2Rs) have been implicated in extraoral functions. Airway smooth muscle expresses TAS2Rs and is strongly relaxed by TAS2R agonists. We hypothesised that TAS2R agonists might affect vascular smooth muscle as well. Moreover, the general pharmacological profile of TAS2R agonists, which are used to investigate the functions of TAS2R׳s, are undefined. The aim of this study was to pharmacologically characterise the effects of five prototype TAS2R agonists in vascular smooth muscle. Responses to the TAS2R agonists were investigated in guinea-pig aorta and taenia coli, mouse aorta (wild-type and caveolin-1(-/-) mice) and human pulmonary arteries. Chloroquine, denatonium, dextromethorphan, noscapine and quinine, agonists for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, induced strong endothelium-independent relaxations (responses between 82-96% of maximal relaxations) in phenylephrine pre-contracted guinea-pig aorta that persisted in the presence of L-type Ca(2+) and KCa1.1-channel blockers. Experiments in guinea-pig taenia coli revealed that denatonium and quinine also inhibited relaxations to phenylephrine, indicating antagonism of α-adrenoceptors. Only chloroquine and noscapine mediated relaxations when the guinea pig aorta was pre-contracted by U-46619 or PGF2α. Relaxations to chloroquine and noscapine after U-46619 pre-contractions were however markedly impaired in aortae from caveolin-1(-/-) mice. Chloroquine and noscapine mediated relaxations of human pulmonary arteries that expressed also mRNA for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, at levels similar to that of the α1A adrenoceptor. Notwithstanding whether TAS2Rs are involved or not, TAS2R agonists have profound effects on vascular smooth muscle. Chloroquine and noscapine are of special interest as their effects cannot be accounted for by conventional pathways