Interaction of drugs and Chinese herbs: pharmacokinetic changes of tolbutamide and diazepam caused by extract of Angelica dahurica.
The inhibitory effects of Angelica dahurica root extract on rat liver microsomal cytochrome P450 and drug-drug interactions were studied. The 2alpha- and 16alpha-hydroxylase activity of testosterone were most strongly inhibited, with 17.2% and 28-5% of their activity remaining, respectively, after oral administration of A. dahurica extract at a 1 g kg(-1) dose. 6beta-Hydroxylase activity was also inhibited, with 70% of its activity remaining, under the same conditions. In addition, treatment with the extract inhibited the metabolism of tolbutamide, nifedipine and bufuralol. These results showed that the extract inhibited the various isoforms of cytochrome P450 such as CYP2C, CYP3A and CYP2D1. The A. dahurica extract delayed elimination of tolbutamide after intravenous administration at a 10 mg kg(-1) dose to rats. Thus, the extract altered the liver intrinsic clearance. It had little effect, however, on the pharmacokinetic parameters of diazepam after intravenous administration at 10 mg kg(-1). Since diazepam showed high clearance, it underwent hepatic blood flow rate-limited metabolism. Therefore, the change of intrinsic clearance had little effect on hepatic clearance. However, the Cmax value after oral administration of diazepam with extract treatment was four times that with non-treatment. It was suggested that the first-pass effect was changed markedly by the extract. High-dose (1 g kg(-1)), but not low dose (0.3 g kg(-1)), administration of A. dahurica extract increased significantly the duration of rotarod disruption following intravenous administration of diazepam at 5 mg kg(-1). It was concluded that administration of A. dahurica extract has the potential to interfere with the metabolism, by liver cytochrome P450, of other drugs.
Ishihara
K
K
Faculty of Pharmaceutical Sciences, Chiba University, Japan. ishihara_kazuhisa@mail.tsumura.co.jp
Kushida
H
H
Yuzurihara
M
M
Wakui
Y
Y
Yanagisawa
T
T
Kamei
H
H
Ohmori
S
S
Kitada
M
M
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D003975:Diazepam / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism; D014044:Tolbutamide / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
D014151:Anti-Anxiety Agents; D004365:Drugs, Chinese Herbal; D007004:Hypoglycemic Agents; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C022724:testosterone 7-alpha-hydroxylase, hamster; D003975:Diazepam