Effect of repeated Shengmai-San administration on nifedipine pharmacokinetics and the risk/benefit under co-treatment

Hong-Jaan Wang ^a,1, Elise Chia-Hui Tan ^b,c,d,1, Tzu-Yi Chiang ^e,f, Wei-Ching Chen ^a, Chien-Chang Shen ^g, Yune-Fang Ueng ^e,f,h,I,*

a School of Pharmacy, National Defense Medical Center, Taipei, Taiwan

b Division of Clinical Chinese Medicine, National Research Institute of Chinese Medicine, Taipei, Taiwan

c Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, Taipei, Taiwan

d Department of Pharmacy, National Yang Ming Chiao Tung University, Taipei, Taiwan

e Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine, Taipei, Taiwan

f Institute of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei,

Taiwan

g Division of Chinese Medicinal Chemistry, National Research Institute of Chinese Medicine, Taipei, Taiwan

h Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

i Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

Herbal interactions with nifedipine/felodipine through cytochrome P450 (CYP) 3A inhibition is significant in humans. Shengmai-San (SMS), a three-herbal formula of Chinese medicine, is commonly prescribed in Asia populations for cardiovascular disorders. This study aimed to elucidate the impact of SMS on nifedipine/felodipine treatment by the findings from rat pharmacokinetic study of nifedipine to the retrospective cohort study of patients with hypertension. The 3-week SMS treatment increased the systemic exposure to nifedipine by nearly two-fold and decreased nifedipine clearance by 39% in rats. Among the ingredients of SMS component herbs, schisandrin B, schisantherin A, and methylophiopogonanone A, inhibited the nifedipine oxidation (NFO) activities of rat hepatic and intestinal microsomes, as well as human CYP3A4. Methylophiopogonanone A was identified as a time-dependent inhibitor of CYP3A4. After 1:5 propensity score matching, 4,894 patients with nifedipine/felodipine use were analyzed. In patients receiving nifedipine/felodipine, the subgroup with concurrent SMS treatment had a higher incidence of headache (92.70 per 1000 person-years) than the subgroup without SMS treatment (51.10 per 1000 person-years). There was a positive association between headache incidence and cumulative doses of SMS (1–60 g SMS: hazard ratio (HR): 1.39; 95% confidence interval (CI): 1.11–1.74; >60 g SMS: HR: 1.97; 95% CI: 1.62–2.39; p < 0.0001). However, patients who had higher cumulative SMS doses had a lower risk of all-cause mortality (1–60 g SMS: HR: 0.67; 95% CI: 0.47–0.94; >60 g SMS: HR: 0.54; 95% CI: 0.37–0.79; p =0.001). Results demonstrated increased rat plasma nifedipine levels after 3-week SMS treatment and increased headache incidence should be noted in nifedipine/felodipine-treated patients with prolonged SMS administration.

Keywords: Clearance, Headache, Methylophiopogonanone A, Nifedipine, Shengmai-San

https://doi.org/10.38212/2224-6614.3401