Effect of troleandomycin on the pharmacokinetics of imipramine in Chinese: the role of CYP3A.
OBJECTIVE
In vitro data indicate that imipramine (IMI), a widely used tricyclic antidepressant drug, is N-demethylated by several isoforms of cytochrome P450, which include CYP3A4. The aim of this study was to investigate the role of CYP3A in the in vivo N-demethylation of IMI.


METHODS
Healthy subjects were given troleandomycin (TAO), a selective inhibitor of CYP3A, 250 mg daily for 2 days before a single oral dose of 100 mg IMI was administered.


RESULTS
Pretreatment with TAO significantly increased the AUC of IMI by 59% (1971 +/- 938 vs 3134 +/- 2000 microg l(-1) h, 95% confidence interval for difference between means: 218 to 2108 microg l(-1) h, P < 0.05) and decreased its oral clearance by 30% (60.9 +/- 27.4 vs 42.5 +/- 22.7 l h(-1), 95% confidence internal for difference between means: 7.2 to 31.7 l h(-1), P < 0.05).


CONCLUSIONS
We conclude that CYP3A may play an important role in the in vivo N-demethylation of IMI.
Wang
J S
JS
Pharmacogenetics Research Institute, Hunan Medical University, Changsha, People's Republic of China.
Wang
W
W
Xie
H G
HG
Huang
S L
SL
Zhou
H H
HH
D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D002681:China; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007099:Imipramine / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012016:Reference Values; D014217:Troleandomycin / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D000929:Antidepressive Agents, Tricyclic; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D007099:Imipramine