Rheumatoid arthritis downregulates the drug transporter OATP1B1: Fluvastatin as a probe

Caris, Juciene Aparecida; Benzi, Jhohann Richard de Lima; Souza, Flávio Falcão Lima de; Oliveira, Renê Donizeti Ribeiro de; Donadi, Eduardo Antônio; Lanchote, Vera Lúcia

doi:10.1016/j.ejps.2020.105264

Cited by 12 publications

(14 citation statements)

References 37 publications

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“…Plasma concentrations of IL-6, IL-8, IL-10, MCP-1, and TNF-α were 1.5-to 2.5fold higher in patients with rheumatoid arthritis compared with healthy individuals while there were no differences in IFN-γ and IL-1β concentrations. 55 Patients with psoriasis have substantially lower inflammation than rheumatoid arthritis with mean IL-6 plasma concentration of 4.2 pg/mL. 56 Accordingly, the pharmacokinetics of a single dose of venlafaxine (CYP2D6 and CYP3A4 substrate) is not different in patients with psoriasis (n = 13) compared with healthy individuals (n = 11).…”

Section: Chronic Inflammatory Diseasesmentioning

confidence: 99%

Clinical and Molecular Perspectives on Inflammation‐Mediated Regulation of Drug Metabolism and Transport

Dunvald

Järvinen

Mortensen

et al. 2021

Clin Pharma and Therapeutics

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Inflammation is a possible cause of variability in drug response and toxicity due to altered regulation in drug‐metabolizing enzymes and transporters (DMETs) in humans. Here, we evaluate the clinical and in vitro evidence on inflammation‐mediated modulation of DMETs, and the impact on drug metabolism in humans. Furthermore, we identify and discuss the gaps in our current knowledge. A systematic literature search on PubMed, Embase, and grey literature was performed in the period of February to September 2020. A total of 203 papers was included. In vitro studies in primary human hepatocytes revealed strong evidence that CYP3A4 is strongly downregulated by inflammatory cytokines IL‐6 and IL‐1β. CYP1A2, CYP2C9, CYP2C19, and CYP2D6 were downregulated to a lesser extent. In clinical studies, acute and chronic inflammatory diseases were observed to cause downregulation of CYP enzymes in a similar pattern. However, there is no clear correlation between in vitro studies and clinical studies, mainly because most in vitro studies use supraphysiological cytokine doses. Moreover, clinical studies demonstrate considerable variability in terms of methodology and inconsistencies in evaluation of the inflammatory state. In conclusion, we find inflammation and pro‐inflammatory cytokines to be important factors in regulation of drug‐metabolizing enzymes and transporters. The observed downregulation is clinically relevant, and we emphasize caution when treating patients in an inflammatory state with narrow therapeutic index drugs. Further research is needed to identify the full extent of inflammation‐mediated changes in DMETs and to further support personalized medicine.

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Section: Chronic Inflammatory Diseasesmentioning

confidence: 99%

Clinical and Molecular Perspectives on Inflammation‐Mediated Regulation of Drug Metabolism and Transport

Dunvald

Järvinen

Mortensen

et al. 2021

Clin Pharma and Therapeutics

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“…Comparing these values to those for IL-6 (mean E min (range) = 0.230 (0.0622 -0.529) and mean EC 50 (range) = 1251 (142 -4070) pg/mL) (Table4; Dickmannet al, 2011) suggests IFN-γ is not as potent a CYP1A2 suppressor as IL-6. It should be noted that the IFN-γ concentrations used in vitro are far in excess of physiological concentrations in healthy subjects (7.5 -21.2 pg/mL or 0.3 ± 0.1 U/mL) and those with RA (17.9 -32.6 pg/mL), acute respiratory infections (3.4 ± 1.3 U/mL)(Brockmeyer et al, 1992;Caris et al, 2020) or acute lymphoblastic leukemia following blinatumomab administration (peak ~ 440 pg/mL)(Xu et al, 2015). Suppression of CYPs by tumor necrosis factor (TNF)-α has been measured in vitro in 5 studies(Abdel-Razzak et al, 1993;Aitken and Morgan, 2007; Dallas et al, 2012, Mimura et al, 2015Klein et al, 2015) Abdel-Razzak et al (1993).…”

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confidence: 99%

Physiologically Based Pharmacokinetic Modeling To Predict Drug-Biologic Interactions with Cytokine Modulators: Are These Relevant and Is Interleukin-6 Enough?

2022

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Introduction: 447Discussion: 4982 Running Title: Cytokine modulated drug interactions Abbreviations: cytochrome P450 (CYP); drug-biologic interactions (DBIs); the U.S. Food and Drug Administration (FDA); drug-drug interactions (DDIs); interleukin (IL); Physiologicallybased pharmacokinetic (PBPK); rheumatoid arthritis (RA); maximum fold suppression (E min ); concentration that supports half-maximal suppression (EC 50 ); interferon (IFN); ethoxyresorufin-O-deethylase (EROD); tumor necrosis factor (TNF); vascular endothelial growth factor (VEGF); area under the curve (AUC); oral clearance (CL po ); human immunodeficiency virus (HIV); monoclonal antibodies (mAb); IL-2 receptor α (IL-2Rα); P-glycoprotein (P-gp); toll-like receptor (TLR); peak concentration (C max ); C-reactive protein (CRP)

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“…Overall, only two studies were retrieved (Table 1 of the ESM) [ 39 , 40 ], and both investigated the inhibitory effect that pro-inflammatory cytokines may have on the OAPT1B1-mediated transport of statins during chronic inflammatory conditions. The first was a case-control PK study that tested the potential influence of a chronic inflammation state on the PK behavior of fluvastatin by comparing the profile of this probe drug of the hepatic sinusoidal OATP1B1 activity between 15 patients with RA and ten healthy volunteers [ 39 ]. Patients with RA had significantly higher median IL-6 levels (11.2 pg/mL vs 4.94 pg/mL; p < 0.05) and TNF-α levels (39.9 pg/mL vs 21.1 pg/mL; p < 0.05) compared with healthy subjects.…”

Section: Resultsmentioning

confidence: 99%

The Cytokine Release Syndrome and/or the Proinflammatory Cytokines as Underlying Mechanisms of Downregulation of Drug Metabolism and Drug Transport: A Systematic Review of the Clinical Pharmacokinetics of Victim Drugs of this Drug–Disease Interaction Under Different Clinical Conditions

Gatti

Pea

2022

Clin Pharmacokinet

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Background and Objective An ever-growing body of evidence supports the impact of cytokine modulation on the patient’s phenotypic drug response. The aim of this systematic review was to analyze the clinical studies that assessed the pharmacokinetics of victim drugs of this drug–disease interaction in the presence of different scenarios of cytokine modulation in comparison with baseline conditions. Methods We conducted a systematic review by searching the PubMed-MEDLINE database from inception until February 2022 to retrieve prospective and/or retrospective observational studies, population pharmacokinetic studies, phase I studies, and/or case series/reports that investigated the impact of cytokine modulation on the pharmacokinetic behavior of victim drugs. Only studies providing quantitative pharmacokinetic data of victim drugs by comparing normal status versus clinical conditions with documented cytokine modulation or by assessing the influence of anti-inflammatory biological agents on metabolism and/or transport of victim drugs were included. Results Overall, 26 studies were included. Rheumatoid arthritis (6/26; 23.1%) and sepsis (5/26; 19.2%) were the two most frequently investigated pro-inflammatory clinical scenarios. The victim drug most frequently assessed was midazolam (14/26; 53.8%; as a probe for cytochrome P450 [CYP] 3A4). Cytokine modulation showed a moderate inhibitory effect on CYP3A4-mediated metabolism (area under the concentration–time curve increase and/or clearance decrease between 1.98-fold and 2.59-fold) and a weak-to-moderate inhibitory effect on CYP1A2, CYP2C9, and CYP2C19-mediated metabolism (in the area under the concentration–time curve increase or clearance decrease between 1.29-fold and 1.97-fold). Anti-interleukin-6 agents showed remarkable activity in counteracting downregulation of CYP3A4-mediated activity (increase in the area under the concentration–time curve between 1.75-fold and 2.56-fold). Conclusions Cytokine modulation may cause moderate or weak-to-moderate downregulation of metabolism/transport of victim drugs, and this may theoretically have relevant clinical consequences. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01173-8.

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Rheumatoid arthritis downregulates the drug transporter OATP1B1: Fluvastatin as a probe

Cited by 12 publications

References 37 publications

Clinical and Molecular Perspectives on Inflammation‐Mediated Regulation of Drug Metabolism and Transport

Clinical and Molecular Perspectives on Inflammation‐Mediated Regulation of Drug Metabolism and Transport

Physiologically Based Pharmacokinetic Modeling To Predict Drug-Biologic Interactions with Cytokine Modulators: Are These Relevant and Is Interleukin-6 Enough?

The Cytokine Release Syndrome and/or the Proinflammatory Cytokines as Underlying Mechanisms of Downregulation of Drug Metabolism and Drug Transport: A Systematic Review of the Clinical Pharmacokinetics of Victim Drugs of this Drug–Disease Interaction Under Different Clinical Conditions

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