In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes (original) (raw)
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Pharmaceutisch Weekblad Scientific Edition, 1988
The pharmacokinetic pararrudters of theophylline and its major metabolites were measured in two healthy volunteers, after the administration of theophylline alone and during co-medication with ofloxacin, 200 mg twice daily, or enoxacin, 200 mg twice daily. During enoxacin co-medication, elimination half-lives of theophylline increased from 8.7 h to I7.4 h and from 6.r h to t2.3 h, respectively. As the renal clearance of theophylline did not change, the decreased elimination of theophylline during enoxacin co-medication must result from a reduced metabolic clearance. Enoxacin co-medication caused a clearly decreased formation of the metabolites i-methyluric acid and 3-methylxanthine, formed by N-demethylation, whereas the C-8 oxidation of theophylline was less influenced compared to the blank. Enoxacin's interference with the theophylline disposition is predominantly based on the inhibition of the microsomal N-demethylation. Ofloxacin co-medication did not induce a change in the plasma parameters or renal excretion of theophylline and its metabolites.
The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects
British Journal of Clinical Pharmacology, 1995
1 The mechanism of the interaction between ciprofloxacin and theophylline was investigated in nine healthy subjects. 2 Subjects were given a single oral dose of theophylline (3.4 mg kg-), before and after 60 h of ciprofloxacin therapy at a dose of 500 mg twice daily. 3 Ciprofloxacin reduced the oral clearance of theophylline by 19% (-7.73 ± 6.42 ml kg-' h-' (95% confidence limits -12.66, -2.79)). Some subjects (group A, n = 4) showed little decrease in clearance (mean 4.4%; -1.6 ± 0.7 ml kg-' h-1 (-2.6, -0.5)), whereas others (group B, n = 5) showed a marked decrease (mean 30%; -12.7 ± 3.7 ml kg-' h-1 (-17.2, -8.1)).
Journal of Pharmaceutical Sciences, 1991
Disposition of diprophylline (DPP) and proxyphylline (PXP) and the effect of enoxacin on their disposition were investigated in rats. Concentrations of the two drugs in plasma and urine were measured by HPLC. The pharmacokinetic parameters of the two drugs were estimated by model-independent methods. Although the chemical structures of the two drugs are very similar, remarkable differences in the disposition of the two drugs were observed. Total body clearance (CL,) of DPP was 1.77 L/h/kg, which was sevenfold greater than that of PXP (0.26 Uh/kg). Diprophylline was excreted in an almost completely unchanged form in the urine, but only 50% of PXP was excreted. However, no binding of either drug to proteins in rat plasma was observed. The DPP renal
Inhibitory Effects of Several Fluoroquinolones on Feline CYP1A and 3A in Hepatic Microsomes
Open Journal of Veterinary Medicine, 2020
In this study, the effects of several fluoroquinolones (FQs), such as Ciprofloxacin (CPFX); Orbifloxacin (OBFX); Norfloxacin (NFX); Ofloxacin (OFX); and Enerofloxacin (EFX) on activities of both Cytochrome P450 1A (CYP1A) and Cytochrome P450 3A (CYP3A) of feline microsomes by in vitro tests were studied. Ethoxyresorufin O-deethylation (EROD) and Midazolam 1' hydroxylation and 4-hydroxylation (MDZ1'H and MDZ4H) were analyzed by High Performance Liquid Chromatography (HPLC). All the FQs inhibited the reactions by a competitive or noncompetitive and irreversible manner. The inhibitory constants (K i) were as followings: CYP1A; ranged from 0.12 to 1.23 mM for NFX, OBFX, EFX, CPFX, OFX and CYP3A, for MDZ1'H; ranged from 5.8 to 35 and MDZ4H; 9 to 29 mM, respectively. As these values are higher by 24 to 200-times of given single clinical dose of serum levels after application of FQs. It indicates that if co-administrated with these FQs by reversible inhibitory manner, the inhibition of CYP1A and CYP3A effect on CYP1A and 3A actions is not very significant to cause drug interaction with above mentioned enzyme substrates. Out of the FQs tested, CPFX and NFX for CYP1A, and CPFX for CYP3A showed irreversible inhibitory effects (time-dependent), so it has been concluded that these drugs may cause drug-drug interaction by accumulation, when they are repeatedly administrated. Since EFX is biotransformed to CPFX by the liver, it could have the identical risk too.
The Effect of Orally Administered Marbofloxacin on the Pharmacokinetics of Theophylline
Journal of Veterinary Medicine Series A, 2003
As certain quinolones can interfere with the metabolism of theophylline by competitive inhibition of the hepatic microsomal cytochrome P450 system, concomitant use of these drugs with theophylline could result in theophylline toxicity. This study investigated the effect of orally administered marbofloxacin (2 and 5 mg/kg each once daily) on steady-state plasma pharmacokinetics of theophylline after concomitant oral administration of a sustained release theophylline preparation in dogs. Marbofloxacin caused some alteration in theophylline metabolism. A 2 mg/kg dose of marbofloxacin did not clearly result in an increased area under the concentration-time curve (AUC) or decreased clearance of theophylline, but at a dose of 5 mg/kg, a statistically significant increase in AUC and a decrease in the total clearance of theophylline was found. The 26% reduction in theophylline clearance is probably not clinically significant in healthy dogs, but for dogs with renal impairment, there might be a chance of theophylline accumulation when dosed concomitantly with marbofloxacin.
Metabolism of theophylline by cDNA-expressed human cytochromes P-450
British Journal of Clinical Pharmacology, 1995
1 Theophylline metabolism was studied using seven human cytochrome P-450 isoforms (CYPs), namely CYPlAl, 1A2, 2A6, 2B6, 2D6, 2E1 and 3A4, and microsomal epoxide hydroxylase (EH), expressed in human B-lymphoblastoid cell lines. 2 At a high theophylline concentration of 10 mm four CYPs (lAl, 1A2, 2D6, 2E1) catalyzed the metabolism of theophylline. 3 Theophylline had the highest affinity (apparent Km range 0.2-1.0 mM) for the CYPIA subfamily and the kinetics of metabolic formation mediated by CYP1A2
The theophylline-enoxacin interaction: I. Effect of enoxacin dose size on theophylline disposition
Clinical pharmacology and therapeutics, 1988
Theophylline interacts pharmacokinetically with a variety of other drugs. Recently enoxacin was found to change theophylline's disposition. In a four-subject, four-way crossover study enoxacin was administered every 12 hours at four levels (0, 25, 100, and 400 mg) for 14 doses. With the ninth dose of enoxacin, 200 mg theophylline was coadministered. Blood and urine samples were assayed by sensitive and specific assays for the parent drugs and their metabolites. Significant reduction in the formation of theophylline's three major metabolites occurred on coadministration of enoxacin. At the 400 mg dose level, enoxacin caused a threefold decrease in theophylline's plasma clearance, a fourfold decrease in the urinary recovery of 3-methylxanthine and 1,3-dimethylurate, and a threefold decrease in the recovery of 1-methylurate.
Adverse Reactions to Fluoroquinolones. An Overview on Mechanistic Aspects
Current Medicinal Chemistry, 2001
This review focuses on the most recent research findings on adverse reactions caused by quinolone antibiotics. Reactions of the gastrointestinal tract, the central nervous system (CNS) and the skin are the most often observed adverse effects. Occasionally major events such as phototoxicity, cardiotoxicity, arthropathy and tendinitis occurr, leading to significant tolerability problems.