Gut Microbiota Affects The Pharmacokinetics Of Nifedipine By Regulating Cyp3a1 In Spontaneously Hypertensive Rats

Background: Nifedipine is a widely used antihypertensive drug,while the pharmacokinetic variability is prevalent in clinical practice.Nifedipine is mainly metabolized by hepatic CYP3A4,but the enzyme activity varies greatly among individuals.PXR is an important nuclear receptor and initiates the expression of CYP3A4 as a transcription factor.Gut microbiota-derived bile acids have been recognized to be endogenous ligand of PXR.It has been reported that gut microbiota can metabolize drugs directly or affect the activity of host drug metabolizing enzymes through their metabolites.Alteration of intestinal flora occurred in patients with hypertension and spontaneously hypertensive rats(SHR),and how it effects the pharmacokinetics of nifedipine needs to be explored.Objective: In this study,we aim to investigate the pharmacokinetics of nifedipine in SHR,and explore the mechanism of gut microbiota regulates Cyp3a1,then affects the pharmacokinetics of nifedipine.Methods: Normotensive Wistar and SHR rats were selected for the pharmacokinetic experiments.Detect the hepatic expression of Cyp3a1 and PXR.Metabolism of nifedipine by host Cyp3a1 enzyme or gut microbiota was studied by coincubation with liver microsomes or fecal bacteria.Gut microbiota compositions and serum bile acids levels were detected.Spearman’s rank correlation test was performed to evaluate the correlations between gut microbiota and bile acids.Furthermore,the inductive effects of bile acids on PXR target genes Cyp3a1 were verified in primary rat hepatocytes.Results:(1)Compared with Wistar,the oral bioavailability of nifedipine decreased significantly in SHR;the liver and kidney functions of two groups were normal.(2)In SHR,the expressions of Cyp3a1 and PXR were up-regulated remarkably,and the enzyme activity of Cyp3a1 increased significantly.(3)Sixteen differential bile acids were found and gut microbiota appeared dysbiosis in SHR.Spearman’s rank correlation revealed that B.stercoris was negatively correlated with GUDCA and GCDCA.Primary rat hepatocytes were treated with GUDCA,GCDCA could induce the expressions of PXR target genes Cyp3a1 and Mdr1 a.Conclusion: In summary,differential Cyp3a1 metabolism altered nifedipine pharmacokinetics in SHR.Moreover,Cyp3a1 was activated possibly depending on a B.stercoris-GUDCA,GCDCA-PXR-Cyp3a1 axis.