Jiao Liu1, Chun-Yan Wang2, Song-Gang Ji2, Xia Xu2, Pei-Pei Wang3, Bin Zhang4, Li-Yan Zhao2, Liang Liu5, Ping-Ping Lin5, Le-Kun Liu6, Ming-Chun Li7. 1. Department of Pharmacy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China. 2. Department of Pharmacy, No. 401 Hospital of Chinese People's Liberation Army, Qingdao, Shandong, China. 3. School of Pharmacy, Fudan University, Shanghai, China. 4. Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. 5. Department of Pharmacology, Medical College of Qingdao University, Qingdao, Shandong, China. 6. Weifang Institute of Dermatology, Weifang, Shandong, China. 7. Department of Pharmacy, No. 401 Hospital of Chinese People's Liberation Army, Qingdao, Shandong, China. lmc401y@163.com.
Abstract
OBJECTIVE: The purpose of the current study was to investigate the effect of the dosing time on the pharmacokinetics of erlotinib and the circadian rhythms of the metabolism enzymes in tumor-bearing mice. METHODS: Female C57BL mice were randomly assigned to six groups. Erlotinib was orally administrated to the mice in each group at six different times of day. The plasma concentration of erlotinib was determined through a high-performance liquid-chromatographic assay, and the total mRNA was extracted from liver tissues to determine the expression of the mRNA of the related drug metabolism enzymes by qRT-PCR. RESULTS: The results indicated that AUC0-24 h and MRT0-24 h were the lowest in the 20:00 group (P < 0.01). T max of the 13 HALO (hour after light onset), 17 HALO and 21 HALO groups was higher than that of the 1 HALO and 5 HALO groups (P < 0.01). CL of the light-phase groups was lower than that of the dark-phase groups (P < 0.01). The peak value of C max appeared in the 5 HALO group (P < 0.01). The mRNA levels of Cyp3a11, Cyp3a13 and Cyp1a2 were generally higher during the afternoon and the dark phase. CONCLUSION: Circadian rhythm plays a critical role in the pharmacokinetics of erlotinib in mice, and the mechanisms may be attributed to gene expression rhythms of drug-metabolizing enzymes in liver tissues.
OBJECTIVE: The purpose of the current study was to investigate the effect of the dosing time on the pharmacokinetics of erlotinib and the circadian rhythms of the metabolism enzymes in tumor-bearing mice. METHODS: Female C57BL mice were randomly assigned to six groups. Erlotinib was orally administrated to the mice in each group at six different times of day. The plasma concentration of erlotinib was determined through a high-performance liquid-chromatographic assay, and the total mRNA was extracted from liver tissues to determine the expression of the mRNA of the related drug metabolism enzymes by qRT-PCR. RESULTS: The results indicated that AUC0-24 h and MRT0-24 h were the lowest in the 20:00 group (P < 0.01). T max of the 13 HALO (hour after light onset), 17 HALO and 21 HALO groups was higher than that of the 1 HALO and 5 HALO groups (P < 0.01). CL of the light-phase groups was lower than that of the dark-phase groups (P < 0.01). The peak value of C max appeared in the 5 HALO group (P < 0.01). The mRNA levels of Cyp3a11, Cyp3a13 and Cyp1a2 were generally higher during the afternoon and the dark phase. CONCLUSION: Circadian rhythm plays a critical role in the pharmacokinetics of erlotinib in mice, and the mechanisms may be attributed to gene expression rhythms of drug-metabolizing enzymes in liver tissues.
Authors: Markus Stratmann; Frédéric Stadler; Filippo Tamanini; Gijsbertus T J van der Horst; Jürgen A Ripperger Journal: Genes Dev Date: 2010-06-15 Impact factor: 11.361