Pharmacokinetics and brain distribution of tetrahydropalmatine and tetrahydroberberine after oral administration of DA-9701, a new botanical gastroprokinetic agent, in rats.
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.
College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea.
Ji Won
JW
Jung
Yong Sam
YS
Kwon
Jin Seok
JS
Jeong
Miwon
M
Son
Hee Eun
HE
Kang
D000284:Administration, Oral; D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D001600:Berberine Alkaloids / Q000097:blood / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D008297:Male; D028321:Plant Preparations / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D001600:Berberine Alkaloids; C533973:DA-9701; D005765:Gastrointestinal Agents; D028321:Plant Preparations; D001599:Berberine; C014215:tetrahydropalmatine; C004645:canadine