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.
Highlights
Recent studies indicate that inflammation may affect CYP3A4 activity
By using alprazolam as a test drug we previously showed that a low degree of inflammation significantly reduced the activity of CYP3A4 [12], which is the most important hepatic drug-metabolizing enzyme accounting for the metabolism of almost 50% of all drugs currently used [13, 14]
We investigated 44 prevalent hemodialysis (HD) patients using quinine as a test drug to investigate the effect of inflammation over four weeks on drug metabolism
Summary
Recent studies indicate that inflammation may affect CYP3A4 activity. Associations of CYP3A4mediated metabolism of quinine, with inflammatory biomarkers were investigated in patients undergoing maintenance hemodialysis (HD). Chronic kidney disease (CKD) patients are at a high risk for drug side effects due to accumulation of drugs, which normally are excreted via the kidneys. It is believed that drugs that are metabolized by the liver are safe to prescribe in normal doses to end-stage renal disease (ESRD) patients. The concentration of many drugs that normally are metabolized by the liver increases significantly in CKD patients. Pro-inflammatory cytokines are thought to be principal mediators of the impact of inflammation on these enzymes and transporters [6]. The mechanism of this inhibitory effect is not clear so far but the transcriptional suppression is thought to be a major factor in the downregulation of many cytochrome P450s and there could
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