Pharmacokinetic study of isocorynoxeine metabolites mediated by cytochrome P450 enzymes in rat and human liver microsomes.
Isocorynoxeine (ICN) is one of the major bioactive tetracyclic oxindole alkaloids found in Uncaria rhynchophylla (Miq.) Jacks. that is widely used for the treatment of hypertension, vascular dementia, and stroke. The present study was undertaken to assess the plasma pharmacokinetic characteristics of major ICN metabolites, and the role of simulated gastric and intestinal fluid (SGF and SIF), human and rat liver microsomes (HLMs and RLMs), and seven recombinant human CYP enzymes in the major metabolic pathway of ICN. A rapid, sensitive and accurate UHPLC/Q-TOF MS method was validated for the simultaneous determination of ICN and its seven metabolites in rat plasma after oral administration of ICN at 40mg/kg. It was found that 18.19-dehydrocorynoxinic acid (DCA) and 5-oxoisocorynoxeinic acid (5-O-ICA) were both key and predominant metabolites, rather than ICN itself, due to the rapid and extensive metabolism of ICN in vivo. The further study indicated that ICN was mainly metabolized in human or rat liver, and CYPs 2C19, 3A4 and 2D6 were the major enzymes responsible for the biotransformation of ICN to DCA and 5-O-ICA in human. These findings are of significance in understanding of the pharmacokinetic nature of tetracyclic oxindole alkaloids, and provide helpful information for the clinical co-administration of the herbal preparations containing U. rhynchophylla with antihypertensive drugs that are mainly metabolized by CYP3A4 and CYP2C19.
Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China.
Lizhu
L
Zhao
Department of Intensive Care Unit, Shengjing Hospital of China Medical University, 36 SanHao Street, Shenyang 110016, People's Republic of China.
Bin
B
Zang
Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China.
Wen
W
Qi
Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China.
Fangfang
F
Chen
School of Pharmaceutical Sciences, Liaoning University of Traditional Chinese Medicine, 77 Shengming 1 Road, DD Port, Dalian 116600, People's Republic of China.
Haibo
H
Wang
Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China.
Yoshihiro
Y
Kano
Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, People's Republic of China. Electronic address: yuandan_kampo@163.com.
Dan
D
Yuan
D000470:Alkaloids / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D026121:Indole Alkaloids / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D032070:Uncaria / Q000737:chemistry
C531543:18,19-dehydrocorynoxinic acid; D000470:Alkaloids; D026121:Indole Alkaloids; C054799:corynoxeine; D003577:Cytochrome P-450 Enzyme System
18.19-dehydrocorynoxinic acid (PubChem CID: 24970642); 18.19-dehydrocorynoxinic acid B (PubChem CID: 24970641); 5-oxoisorhynchophyllic acid (PubChem CID: 102004526); Corynoxeine (PubChem CID: 44568160); Cytochrome P450s; Human; Isocorynoxeine; Isocorynoxeine (PubChem CID: 5316103); Pharmacokinetics; Rat; UHPLC/Q-TOF MS; Uncaria rhynchophylla