The influence of a newly developed quinolone: antofloxacin, on CYP activity in rats.
To investigate a newly developed quinolone antibiotics, the effect of antofloxacin hydrochloride on cytochrome P450 isoforms in rats was examined. A cocktail approach was adopted. Theophylline (CYP1A2), midazolam (CYP3A), chlorzoxazone (CYP2E1), dextromethorphan (CYP2D6), omeprazole (CYP2C19) and diclofenac (CYP2C9) were used as probes in the study, and own control was adopted. In Protocol 1, probes were given to rats simultaneously by co-administration with antofloxacin. The blood samples were obtained at designated time, and plasma concentrations of the six probes were determined by LC-MS. The pharmacokinetic parameters were calculated and compared in experimental groups in the absence and presence of antofloxacin. The result showed that the presence of antofloxacin resulted in a significant increase in theophylline values of AUC0-T and t1/2 (PAUC0-T = 0.0004 vs control Pt1/2 = 0.005 vs control), indicating that antofloxacin delayed the clearance of theophylline. In Protocol 2, the probes' pharmacokinetic parameters were compared in rats that received six probes before and after 14.5 days of consecutive administration of antofloxacin (15 mg x kg(-1), given orally, twice daily). The results suggested that the AUC0-T of chlorzoxazone was significantly decreased (P = 0.024), while that of dextromethorphan was significantly increased (P = 0.027). In conclusion, these results indicated that antofloxacin may inhibit the activity of CYP1A2, thus delaying the clearance of its substrates, and may have a slight inhibitory effect on CYP2D6 as well as an inductive effect on CYP2E1 following chronic administration.
Xu
Xiao
X
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People's Republic of China.
Liu
Hai-Yan
HY
Liu
Li
L
Xie
Lin
L
Liu
Xiao-Dong
XD
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D002753:Chlorzoxazone / Q000097:blood / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000097:blood / Q000493:pharmacokinetics; D004008:Diclofenac / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D015242:Ofloxacin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000097:blood / Q000493:pharmacokinetics
D000900:Anti-Bacterial Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D004008:Diclofenac; C522674:antofloxacin; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D015242:Ofloxacin; D013806:Theophylline; D002753:Chlorzoxazone; D009853:Omeprazole; D008874:Midazolam