Age-dependent pharmacokinetics of nifedipine in spontaneous hypertensive rats are associated with changes in gut microbiota and hepatic CYP3A1 expression

Despite nifedipine's satisfactory efficacy, patients with higher blood pressure often require combination therapy or increased dosages. The reasons for the reduced efficacy of nifedipine in this population remain unclear. Here, this study aimed to explore whether there are differences in nifedipine pharmacokinetics among rats with different blood pressure level and to assess the role of gut microbiota in this process. Spontaneously hypertensive rats (SHR) at 8, 12, and 16 weeks and age-matched Wistar-Kyoto (WKY) rats were used to study the pharmacokinetics of nifedipine. The WKY rats were used as the control group. We examined the pharmacokinetics of nifedipine in both SHR and WKY rats of different ages, analyzing the composition of gut microbiota and the bile acids profile in these age groups. The area under the concentration-time curve and C_max of nifedipine in SHR decreased progressively with age. Compared with 8-week-old SHR, the expression of CYP3A1 in the liver was significantly upregulated in both 12-week-old and 16-week-old SHR. Five Bacterial genera potentially related to the pharmacokinetics of nifedipine were identified: Romboutsia, the Lachnospiraceae_NK4A136_group, Alistipes, Anaerostipes, and Ruminococcaceae_UCG-013. We found that 8 bile acids, including cholic acid, ursodeoxycholic acid, glycocholic acid, taurolithocholic acid, glycolithocholic acid, glycoursodeoxycholic acid, glycochenodeoxycholic acid, and tauro-β-muricholic acid, were reduced with increasing age in SHR. In conclusion, our results suggest that there are significant differences in nifedipine pharmacokinetics among SHR of different blood pressure. The increasing expression of CYP3A1 in the liver and direct metabolism of gut microbiota were likely the main reasons. SIGNIFICANCE STATEMENT: This study explores blood pressure-dependent differences in nifedipine pharmacokinetics in spontaneously hypertensive rats and reveals the roles of liver enzyme expression and gut microbiota metabolism in the process. Understanding these factors is crucial for addressing disease-related variability in drug efficacy and resistance, offering insights that could enhance personalized treatment strategies for hypertension and Other associated diseases.

Bile acids; CYP3A1; Farnesoid X receptor; Gut microbiota; Hypertension; Nifedipine.