title: Characterization of human metabolism and disposition of levo-tetrahydropalmatine: Qualitative and quantitative determination of oxidative and conjugated metabolites.
abstract: Levo-tetrahydropalmatine (l-THP) is a tetrahydroprotoberberine isoquinoline alkaloid and has been used as an analgesic agent in China for over 50 years. Recent studies revealed that l-THP was effective in the treatment of drug addiction. However, the plasma metabolic profile, mass balance and clearance pathways of l-THP in human remain unknown. In the present study, an analytical strategy was developed for qualitative and quantitative investigation of metabolism and disposition of l-THP in human. Detection and structural characterization of l-THP metabolites were performed using liquid chromatography-quadrupole time-of-flight mass spectrometry. Selected major metabolites in plasma, urine and feces determined by liquid chromatography with UV detection were further quantified using a triple quadruple mass spectrometry and reference standards. A total of 20 metabolites were identified, most of which were formed via demethylation, mono-hydroxylation, and glucuronidation and sulfonation of desmethyl metabolites. Five major metabolites accounted for over 10% of the parent drug concentration in plasma. Major urinary and fecal metabolites and the parent drug that were monitored for 72h accounted for 46.3% of the dose, while only 0.16% of the dose was the unchanged drug. Multiple demethylations followed by glucuronide and sulfate conjugations and renal excretion were the major drug clearance pathways of l-THP in human.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China; State Key Laboratory of Toxicology and Medical Countermeasures, China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China; Chinese Academy of Inspection and Quarantine, Beijing China, China.
authors.forename: Guolin
authors.initials: G
authors.lastname: Shen
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China; State Key Laboratory of Toxicology and Medical Countermeasures, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: Agilent Technologies, Beijing, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Ran
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA. Electronic address: mingshe.zhu@bms.com.
authors.forename: Mingshe
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China; State Key Laboratory of Toxicology and Medical Countermeasures, China. Electronic address: amms_hli@126.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
mesh_terms: D000328:Adult; D001600:Berberine Alkaloids / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D006801:Humans; D008297:Male; D053719:Tandem Mass Spectrometry
chemical_list: D001600:Berberine Alkaloids; C014215:tetrahydropalmatine
keywords: Disposition; Human; LC–MS/MS; Levo-tetrahydropalmatine; Metabolism; QTOF-MS/MS