Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats

Abstract

Aim: Caderofloxacin is a new fluoroquinolone that is under phase III clinical trials in China. Here we examined the effects of caderofloxacin on rat hepatic cytochrome P450 (CYP450) isoforms as well as the potential of caderofloxacin interacting with co-administered drugs. Methods: Male rats were treated with caderofloxacin (9 mg/kg, ig) once or twice daily for 14 consecutive days. The effects of caderofloxacin on CYP3A, 2D6, 2C19, 1A2, 2E1 and 2C9 were evaluated using a "cocktail" of 6 probes (midazolam, dextromethorphan, omeprazole, theophylline, chlorzoxazone and diclofenac) injected on d 0 (prior to caderofloxacin exposure) and d 15 (after caderofloxacin exposure). Hepatic microsomes from the caderofloxacin-treated rats were used to assess CYP2E1 activity and chlorzoxazone metabolism. The expression of CYP2E1 mRNA and protein in hepatic microsomes was analyzed with RT-PCR and Western blotting, respectively. Results: Fourteen-day administration of caderofloxacin significantly increased the activity of hepatic CYP2E1, leading to enhanced metabolism of chlorzoxazone. In vitro microsomal study confirmed that CYP2E1 was a major metabolic enzyme involved in chlorzoxazone metabolism, and the 14-d administration of caderofloxacin significantly increased the activity of CYP2E1 in hepatic microsomes, resulting in increased formation of 6-hydroxychlorzoxazone. Furthermore, the 14-d administration of caderofloxacin significantly increased the expression of CYP2E1 mRNA and protein in liver microsomes, which was consistent with the pharmacokinetic results. Conclusion: Fourteen-day administration of caderofloxacin can induce the expression and activity of hepatic CYP2E1 in rats. When caderofloxacin is administered, a potential drug-drug interaction mediated by CYP2E1 induction should be considered.

Food–Drug Interaction between the Adlay Bran Oil and Drugs in Rats

“…The calibration curves were linear over a concentration range of 100 to 15,000 ng/mL for theophylline, 50 to 15,000 ng/mL for diclofenac, 2.67 to 2000 ng/mL for dextromethorphan, 2.5 to 1500 ng/mL for chlorzoxazone, and 1.67 to 1000 ng/mL for diltiazem with correlation coefficients ≥ 0.995. The plasma concentrations of five probe drugs were analyzed by HPLC/MS that had good accuracy (greater than 90%) and precision (less than 5%) as described previously [24,29].…”

“…Experiment I: To investigate whether a single oral dose of ABO could affect the plasma drug levels when administered of the drug cocktail intravenously (through the rat tail vein) or orally (via an intragastric tube). The drug cocktail consisted of five in vivo specific CYP probe drugs, including theophylline, diclofenac, dextromethorphan, chlorzoxazone, and diltiazem for the evaluation of CYP1A2, 2C, 2D, 2E1, and 3A isozyme activity, respectively [24,25]. Male Sprague–Dawley (SD) rats, weighing about 300 g each (8–10 weeks old) and cannulated (PE-50) in the jugular vein, were obtained from BioLASCO, Ilan, Taiwan.…”

“…However, whether ABO can affect the plasma drug concentration when administered concomitantly with a drug remains unknown. In this study, rats were given a single oral dose of ABO or consecutive feeding with an ABO-containing diet for 7 days, and then were administered a drug cocktail to investigate the possible food–drug interaction between the adlay bran oil and five cytochrome P450 probe drugs, theophylline (CYP1A2), diclofenac (CYP2C), dextromethorphan (CYP2C), chlorzoxazone (CYP2E1), and diltiazem (CYP3A), in rats [24,25]. Results from this study showed that a single oral dose or short-term administration of ABO may increase plasma drug concentrations when ABO is given concomitantly with drugs.…”

The Influence of Long-Term Treatment with Asenapine on Liver Cytochrome P450 Expression and Activity in the Rat. The Involvement of Different Mechanisms

“…The flow rate was 1.0 mL/min from 0-8 min, 1.5 mL/min from 8.1-14 min and 14.1-15 min from 1.0 mL/min. The analytical wavelength was 287 nm and the column temperature was 25 • C. Total analysis time was 15 min and the retention time of 6-hydroxychlorzoxazone and chlorzoxazone was 4.5 and 13.5 min, respectively [66,67]. The sensitivity of the method allowed for quantification of chlorzoxazone and 6-hydroxychlorzoxazone as low as 0.004 nmol and 0.003 nmol in one sample, respectively.…”

Recent Developments in the Synthetic Strategies of 4‐Quinolones and Its Derivatives

“…[14][15] In addition to the above, now they are widely explored as anti-HIV, [16] antimalarial agents, [17,18] alkaline phosphatase inhibitors, [19] antifilarial agents, [20] and antidiabetic agent, [21] for the development of novel therapeutic agents. Different drugs containing quinolone nucleus such as caderofloxacin lactate, [22] DX-619, [23] 259 C, [24] GSK945237, [25] MCB3681, [26][27] WCK-1152, [28] nemonoxacin, delafloxacin" [29][30] voreloxin, [31] (figure 2), etc. are under different phases of clinical trials for various activities such as antibacterial activity, topoisomerase inhibitory activity, DNA gyrase inhibitory activity, community-acquired pneumonia, etc.…”