Pharmacokinetics and brain distribution of tetrahydropalmatine and tetrahydroberberine after oral administration of DA-9701, a new botanical gastroprokinetic agent, in rats.

Abstract

DA-9701, a new botanical gastroprokinetic agent, has potential for the management of delayed gastric emptying in Parkinson's disease if it has no central anti-dopaminergic activity. Therefore, we examined the pharmacokinetics of DA-9701 components having dopamine D2 receptor antagonizing activity, tetrahydropalmatine (THP) and tetrahydroberberine (THB), following various oral doses (80-328 mg/kg) of DA-9701. The distribution of THP and THB to the brain and/or other tissues was also evaluated after single or multiple oral administrations of DA-9701. Oral administration of DA-9701 yielded dose-proportional area under the plasma concentration-time curve (AUC0-8 h) and maximum plasma concentration (Cmax) values for THP and THB, indicating linear pharmacokinetics (except for THB at the lowest dose). THP and THB's large tissue-to-plasma concentration ratios indicated considerable tissue distribution. High concentrations of THP and THB in the stomach and small intestine suggest an explanation for DA-9701's potent gastroprokinetic activity. The maximum concentrations of THP and THB in brain following multiple oral DA-9701 for 7 d (150 mg/kg/d) was observed at 30 min after the last oral DA-9701 treatment: 131±67.7 ng/g for THP and 6.97±4.03 ng/g for THB. Although both THP and THB pass through the blood-brain barrier, as indicated by brain-to-plasma concentration ratios greater than unity (approximately 2-4), oral administration of DA-9701 at the effective dose in humans is not expected to lead to sufficient brain concentrations to exert central dopamine D2 receptor antagonism.

• Authors: Ji Won Jung, Yong Sam Kwon, Jin Seok Jeong, Miwon Son, Hee Eun Kang
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 38 Issue 2 Pg. 285-91 ( 2015) ISSN: 1347-5215 [Electronic] Japan
• PMID: 25747988 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Berberine Alkaloids
• DA-9701
• Gastrointestinal Agents
• Plant Preparations
• Berberine
• tetrahydropalmatine
• canadine

Topics

• Administration, Oral
• Animals
• Berberine (analogs & derivatives, blood, pharmacokinetics)
• Berberine Alkaloids (blood, pharmacokinetics)
• Brain (metabolism)
• Gastrointestinal Agents (pharmacology)
• Male
• Plant Preparations (pharmacology)
• Rats, Sprague-Dawley
• Tissue Distribution