Shenmai-Yin decreased the clearance of nifedipine in rats: The involvement of time-dependent inhibition of nifedipine oxidation

Hong-Jaan Wang ^a, Chung-Kuang Lu ^b,e, Wei-Ching Chen ^a, An-Chi Chen ^c,f, Yune-Fang Ueng ^c,d,f,g,*

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

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

^c Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine, Taipei, Taiwan

^d Department of Pharmacy and Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan

^e Department of Life Sciences and Institute of Genome Sciences, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan

^f Institute of Biopharmaceutical Sciences, School of Pharmacy, National Yang-Ming University, Taipei, Taiwan

^g Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan

The traditional Chinese herbal formula Shenmai-Yin (SY) and nifedipine have both been used to treat patients with cardiovascular disorders. Nifedipine is primarily oxidized by cytochrome P450 (CYP) 3A. The oxidation and pharmacokinetics of nifedipine were studied in rats in vitro and in vivo to illustrate the interaction of SY with nifedipine. Schisandrol A, schisandrin A and schisandrin B were identified as the main lignans in SY. In the study in vitro, the ethanolic extract of SY was used due to the solubility and the extract inhibited nifedipine oxidation (NFO) activity in a time-dependent manner. Among lignans, schisandrin B caused the most potent inhibition. According to the time-dependent inhibition behavior, rats were treated with SY 1 h before nifedipine administration. After oral treatment with 1.9 g/kg SY, nifedipine clearance decreased by 34% and half-life increased by 142%. SY treatment decreased hepatic NFO activity by 49%. Compared to the change caused by ketoconazole, the SY-mediated reduction of nifedipine clearance was moderate. These findings demonstrate that SY causes a time-dependent inhibition of NFO and schisandrin B contributes to the inhibition. The decreased nifedipine clearance by SY in rats warrants further human study to examine the clinical impact of this decrease.

Keywords: Clearance, Cytochrome P450, Nifedipine, Shenmai-Yin, Time-dependent inhibition