Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects.
OBJECTIVE
This study was designed to define the effect of low-dose aspirin administration on the activity of cytochrome P450 (CYP) in normal human subjects.


METHODS
Aspirin, 50 mg daily, was given for 14 days to 18 nonsmoking healthy male volunteers. A modified 5-drug cocktail procedure consisting of caffeine, mephenytoin, metoprolol, chlorzoxazone, and midazolam was performed to simultaneously assess in vivo activity of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A, respectively. The activities were assessed on 4 occasions including at baseline, after 7 and 14 daily doses of aspirin, and at 7 days after discontinuation of aspirin. Concentrations of parent drugs and corresponding metabolites in biologic samples were assayed by reversed-phase HPLC.


RESULTS
Both 7-day and 14-day aspirin intake increased the activity of CYP2C19 significantly, as indicated by 4-hydroxymephenytoin urinary recovery (P <.001). Induction of low-dose aspirin on CYP2C19 was time-dependent. CYP3A activity indices increased moderately but significantly by both 7-day and 14-day aspirin treatment (P <.05), but the percentage changes in CYP3A activity indices were not significant. Low-dose aspirin had no effect on CYP1A2, CYP2D6, and CYP2E1 in vivo activity by either 7-day or 14-day treatment.


CONCLUSIONS
The effect of low-dose aspirin on CYPs was enzyme-specific. Both 7-day and 14-day low-dose aspirin induced the in vivo activities of CYP2C19 but did not affect the activities of CYP1A2, CYP2D6, and CYP2E1. The effect of low-dose aspirin on CYP3A activity awaits further confirmation. When low-dose aspirin is used in combination with drugs that are substrates of CYP2C19, doses of the latter should be adjusted to ensure their efficacy.
Chen
Xiao-Ping
XP
Pharmacogenetics Research Institute, Central South University, Changsha, Hunan 410078, PR China.
Tan
Zhi-Rong
ZR
Huang
Song-Lin
SL
Huang
Zheng
Z
Ou-Yang
Dong-Sheng
DS
Zhou
Hong-Hao
HH
D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D001241:Aspirin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D002110:Caffeine / Q000097:blood; D002681:China; D002753:Chlorzoxazone / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008617:Mephenytoin / Q000031:analogs & derivatives* / Q000652:urine; D008790:Metoprolol / Q000652:urine; D008874:Midazolam / Q000097:blood; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010641:Phenotype; D012016:Reference Values; D013806:Theophylline / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D002110:Caffeine; C025687:4-hydroxymephenytoin; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008790:Metoprolol; D002753:Chlorzoxazone; C021183:1,7-dimethylxanthine; D001241:Aspirin; D008617:Mephenytoin; D008874:Midazolam