Effect of Gut Microbiota on the Pharmacokinetics of Nifedipine in Spontaneously Hypertensive Rats

Author:

Zhou Rong1234,Yang Haijun1234,Zhu Peng1234,Liu Yujie1234,Zhang Yanjuan1234,Zhang Wei1234,Zhou Honghao1234,Li Xiong5,Li Qing1234ORCID

Affiliation:

1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China

2. Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China

3. Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, China

4. National Clinical Research Center for Geriatric Disorders, Changsha 410008, China

5. Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510699, China

Abstract

The pharmacokinetic variability of nifedipine widely observed in the clinic cannot be fully explained by pharmacogenomics. As a new factor affecting drug metabolism, how the gut microbiota affects the pharmacokinetics of nifedipine needs to be explored. Spontaneously hypertensive rats (SHRs) have been commonly used in hypertension-related research and served as the experimental groups; Wistar rats were used as control groups. In this study, the bioavailability of nifedipine decreased by 18.62% (p < 0.05) in the SHRs compared with the Wistar rats. Changes in microbiota were associated with the difference in pharmacokinetics. The relative abundance of Bacteroides dorei was negatively correlated with AUC0–t (r = −0.881, p = 0.004) and Cmax (r = −0.714, p = 0.047). Analysis of serum bile acid (BA) profiles indicated that glycoursodeoxycholic acid (GUDCA) and glycochenodeoxycholic acid (GCDCA) were significantly increased in the SHRs. Compared with the Wistar rats, the expressions of CYP3A1 and PXR were upregulated and the enzyme activity of CYP3A1 increased in the SHRs. Spearman’s rank correlation revealed that Bacteroides stercoris was negatively correlated with GUDCA (r = −0.7126, p = 0.0264) and GCDCA (r = −0.6878, p = 0.0339). Moreover, GUDCA was negatively correlated with Cmax (r = −0.556, p = 0.025). In primary rat hepatocytes, GUDCA could induce the expressions of PXR target genes CYP3A1 and Mdr1a. Furthermore, antibiotic treatments in SHRs verified the impact of microbiota on the pharmacokinetics of nifedipine. Generally, gut microbiota affects the pharmacokinetics of nifedipine through microbial biotransformation or by regulating the enzyme activity of CYP3A1.

Funder

National Natural Science Foundation (NNSF) of China

National Key Research and Development Program of China

National Key Clinical Specialty Construction Project

High-Level Clinical Key Specialty

Publisher

MDPI AG

Subject

Pharmaceutical Science

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