Effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, in healthy subjects.
BACKGROUND
Woohwangcheongsimwon suspension has traditionally been used for the treatment and prevention of stroke, hypertension, palpitations, convulsions and unconsciousness in various Asian countries. Woohwangcheongsimwon suspensions showed an inhibitory effect on CYP2B6 activity in vitro. Two terpenoids, borneol and isoborneol, are major constituents of woohwangcheongsimwon suspension, and show a competitive inhibition of CYP2B6 with K(i) values of 9.5 and 5.9 microM, respectively. Bupropion undergoes metabolic transformation to the active metabolite, 4-hydroxybupropion, primarily via CYP2B6 both in vivo and in vitro. It is often used as a CYP2B6 substrate for clinical drug-drug interaction studies. Drug interactions may occur between woohwangcheongsimwon suspension and bupropion.


CONCLUSIONS
Co-administration with woohwangcheongsimwon suspension did not alter the pharmacokinetics of bupropion or its metabolite, 4-hydroxybupropion. Dosage adjustment of bupropion is unnecessary in patients concomitantly administered the highest recommended daily dose of woohwangcheongsimwon suspension.


OBJECTIVE
To examine the effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, formed via CYP2B6 in vivo.


METHODS
A two-way crossover clinical trial with a 2 week washout period was conducted in 14 healthy volunteers. In phases I and II, subjects received 150 mg bupropion with or without woohwangcheongsimwon suspension four times (at -0.17, 3.5, 23.5 and 47.5 h, with the time of bupropion administration taken as 0 h) in a randomized balanced crossover order. Bupropion and 4-hydroxybupropion plasma concentrations were measured for up to 72 h by LC-MS/MS. Urine was collected up to 24 h to calculate the renal clearance. In addition, the CYP2B6*6 genotype was also analyzed.


RESULTS
The geometric mean ratios and 90% confidence interval of bupropion with woohwangcheongsimwon suspension relative to bupropion alone were 0.976 (0.917, 1.04) for AUC(0,infinity) and 0.948 (0.830,1.08) for C(max), respectively. The corresponding values for 4-hydroxybupropion were 0.856 (0.802, 0.912) and 0.845 (0.782, 0.914), respectively. The t(max) values of bupropion and 4-hydroxybupropion were not significantly different between the two groups (P > 0.05). The pharmacokinetic parameters of bupropion and 4-hydroxybupropion were unaffected by woohwangcheongsimwon suspension.


CONCLUSIONS
These results indicate that woohwangcheongsimwon suspension has a negligible effect on the disposition of a single dose of bupropion in vivo. As a result, temporary co-administration with woohwangcheongsimwon suspension does not seem to require a dosage adjustment of bupropion.
Kim
Hyunmi
H
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
Bae
Soo Kyung
SK
Park
Soo-Jin
SJ
Shim
Eon-Jeong
EJ
Kim
Ho-Sook
HS
Shon
Ji-Hong
JH
Liu
Kwang-Hyeon
KH
Shin
Jae-Gook
JG
D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D016642:Bupropion / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065702:Cytochrome P-450 CYP2B6; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D041743:Herb-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D013535:Suspensions; D055815:Young Adult
D018687:Antidepressive Agents, Second-Generation; D004365:Drugs, Chinese Herbal; D013535:Suspensions; D016642:Bupropion; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C496215:radafaxine