Inflammation down-regulates CYP3A4-catalysed drug metabolism in hemodialysis patients

Abstract

BackgroundRecent studies indicate that inflammation may also affect CYP3A4 activity. Associations of CYP3A4-mediated metabolism of quinine, with inflammatory biomarkers were investigated in patients undergoing maintenance hemodialysis (HD).MethodsA single dose of 100 mg quinine was given to 44 HD patients and the plasma concentration of quinine and its metabolite 3-OH-quinine were measured 12 h after drug intake. The ratios of quinine/3-OH-quinine and 4β-OH-cholesterol/cholesterol were used as markers of CYP3A4 activity. Inflammatory biomarkers, high-sensitive CRP (hsCRP), pentraxin 3 (PTX3) and orosomucoid were followed during 4 weeks prior to quinine administration.ResultsThe quinine/3-OH-quinine ratio correlated with median concentrations of hsCRP (Rho = 0.48; p = 0.001) and orosomucoid (Rho = 0.44; p = 0.003), and also with interleukin-6 at 12 h after drug intake (Rho = 0.43; P = 0.004) but not PTX3. In multivariate regression analysis, the correlation between CYP3A4 activity and median hsCRP remained borderline significant (p = 0.05). 4β-OH-cholesterol/cholesterol ratio correlated with quinine/3-OH-quinine (p = 0.008), but not with any of the inflammation markers.ConclusionsThe association between CYP3A4 activity and inflammatory biomarkers suggest that the activity of CYP3A4 is reduced by inflammation in HD patients. Further studies are needed to confirm this finding and to assess to what extent magnitude and duration of inflammation as well as the microbiota affect drug metabolism.

Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations

“…In patients with COVID-19, the risks of drug–drug interactions involving psychotropic medications might be relevant. Firstly, the bioavailability and disposition of several psychotropic medications might be importantly affected by COVID-19-related systemic inflammation processes [ 65 ], impaired liver functioning [ 35 ], and abrupt smoking cessation [ 45 , 46 , 64 ]. Secondly, psychotropic medications and medical treatments can reciprocally affect each other’s plasma levels by inducing or inhibiting cytochrome P450 (CYP) activity to an extent which is poorly understood and hardly predictable [ 37 ].…”

Impact of Acute Inflammation on Cytochromes P450 Activity Assessed by the Geneva Cocktail

“…Previous publications have demonstrated that infection and more broadly inflammation decreased CYP3A activity, and in proportion to the severity of the disease 5,11,14,24,25 . Moreover, authors have shown that CYP3A4 activity was inversely correlated to CRP levels 26,27 . Surgery and cancer have also been associated with decreased CYP3A4 activity and increased serum levels of CRP and IL‐6, respectively 9,10 .…”

“…5,11,14,24,25 Moreover, authors have shown that CYP3A4 activity was inversely correlated to CRP levels. 26,27 Surgery and cancer have also been associated with decreased CYP3A4 activity and increased serum levels of CRP and IL-6, respectively. 9,10 Moreover, in patients with rheumatoid arthritis, when inflammation was reversed by tocilizumab, an anti-IL-6 receptor antibody, exposure to simvastatin was significantly reduced by half at 1 and 5 weeks after infusion.…”

Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment

“…However, data are still lacking to accurately describe the impact of each factor in this multifactorial change. The impact of inflammation on CKD patients has been independently investigated in only one study, using alprazolam as a probe drug for CYP3A4 activity ( Molanaei et al, 2018 ). The ratio of alprazolam to 4-hydroxyalprazolam correlated with CRP concentrations in 26 hemodialysis patients, suggesting the downregulation of CYP3A4 activity by inflammation.…”