Inhibition of the oxidative metabolism of theophylline in isolated rat hepatocytes by the quinolone antibiotic enoxacin and its metabolite oxoenoxacin, but not by ofloxacin

Mulder, Gerard J.; Nagelkerke, J. Fred; Tijdens, Roeline B.; Wijnands, W. J. A.; Mark, E. J. van der

doi:10.1016/0006-2952(88)90247-x

Cited by 20 publications

(9 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…13,14 Many interactions between ciprofloxacin and other drugs, metabolised by hepatic cytochrome P450 isoenzymes, have been identified. [15][16][17]20,21,32 Thus, it has been established that ciprofloxacin is an inhibitor of cytochrome P450 3A2 activity in vitro and in vivo. [16][17][18][19][20] Since CYP3A2 is involved in both pathways, that is, activation and deactivation of CY, a decreased clearance and subsequently a decreased metabolic ratio (AUC 4ÀOHÀCY /AUC CY ) caused by ciprofloxacin would be expected.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Alteration of pharmacokinetics of cyclophosphamide and suppression of the cytochrome P450 genes by ciprofloxacin

Xie

Griškevičius

Broberg

et al. 2003

Bone Marrow Transplant

View full text Add to dashboard Cite

Summary:Recently, it has been reported that prophylactic administration of ciprofloxacin during cyclophosphamide (CY) conditioning was a high-risk factor for relapse in patients undergoing allogeneic BMT. In the present study, we investigated the possible mechanisms of this interaction in male Sprague-Dawley rats. The kinetics of CY and its active 4-OH-CY metabolite were determined, after 3 days pretreatment with ciprofloxacin (200 mg/kg) and compared to control rats without treatment. CY was administered as a high or low single intravenous dose (150 and 90 mg/kg, respectively). The expression of the CYP2B1, CYP2B2, CYP2C11, CYP3A1 and CYP3A2 genes was evaluated by SYBR Green I Dye real-time PCR for quantification of mRNA. The administration of ciprofloxacin resulted in a significant increase in the AUC (P ¼ 0.007) and a significant decrease in clearance (P ¼ 0.007) when CY was given as a high dose. In accordance, the metabolic ratio (AUC4-OH-CY/ AUCCY) was significantly lower (P ¼ 0.007) compared to that found in the control group. Ciprofloxacin significantly suppressed gene expression of CYP2C11 (P ¼ 0.01) and CYP3A1 (P ¼ 0.04); however, no effect was observed on the gene expression of CYP3A2, CYP2B1 and CYP2B2. Our study revealed that ciprofloxacin interacts with CY and suppressed relevant cytochromes P450 at the transcriptional level. This study may have a great clinical impact when ciprofloxacin is used in therapy. Bone Marrow Transplantation (2003Transplantation ( ) 31, 197-203. doi:10.1038 Keywords: cyclophosphamide; ciprofloxacin; interaction; cytochrome P450; gene expression; bone marrow transplantation Cyclophosphamide (CY) is a prodrug, which requires hepatic biotransformation to exert its cytotoxic effect. 1 An alternative but minor pathway is the inactivation of CY and both pathways are dependent on cytochrome P450 enzymes. [2][3][4][5] In humans, CYP2B6 is the main catalyst of CY activation, along with the contribution from CYP2C, CYP3A4, and CYP2A6 isoenzymes. 5-7 CY inactivation is mostly catalysed by CYP3A4. 5 In noninduced male rats, the constitutively expressed CYP2C11 and CYP3A2 are the major enzymes involved in CY bioactivation, while the inducible CYP2B1 was shown to be a major catalyst of CY activation in induced rats. 2,4 Thus, in vivo or in vitro alteration of hepatic CYPs could change the rate and pattern of CY metabolism. 8 Concomitant use of CY with other drugs that are inhibitors or inducers of CYP2B, CYP2C, or CYP3A enzymes could cause interactions. [9][10][11][12] Ciprofloxacin is a DNA gyrase inhibitor used as an antibacterial drug. 13 This fluoroquinolone agent has gained widespread use in the treatment of a broad range of infections. 14 Investigations focused on drug interactions between ciprofloxacin and other drugs have been reported in recent years. Particularly, interactions between ciprofloxacin and drugs metabolised by the hepatic cytochrome P450 (CYP) system have attracted attention. 15 Studies with hepatic microsomes demonstrated that ciprofloxacin can decrease CYP3A-me...

show abstract

Section: Discussionmentioning

confidence: 99%

“…17 It was also shown that ciprofloxacin is an inhibitor of cytochrome P4501A2 activity in vitro and in vivo. 18 Interactions between ciprofloxacin and theophylline 19,20 or caffiene 18 have been identified. In addition, adverse reaction of CYP-metabolized warfarin was reported because of coadministration of fluoroquinolone agents.…”

mentioning

confidence: 99%

Alteration of pharmacokinetics of cyclophosphamide and suppression of the cytochrome P450 genes by ciprofloxacin

Xie

Griškevičius

Broberg

et al. 2003

Bone Marrow Transplant

View full text Add to dashboard Cite

show abstract

“…Wijnands et al suggested (27) that the oxo metabolite of enoxacin, oxo-enoxacin, might be responsible for this inhibition. However, subsequent in vitro studies with rat hepatocytes indicate that only the parent compound inhibits theophylline metabolism (9). The aim of the present investigation is to * Corresponding author.…”

mentioning

confidence: 99%

In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes

Sarkar

Polk

Guzelian

et al. 1990

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Some quinolone antibiotics cause increases in levels of theophylline in plasma that lead to serious adverse effects. We investigated the mechanism of this interaction by developing an in vitro system of human liver microsomes. Theophylline (1,3-dimethylxanthine) was incubated with human liver microsomes in the presence of enoxacin, ciprofloxacin, norfloxacin, or ofloxacin. Theophylline, its demethylated metabolites (3-methylxanthine and 1-methylxanthine), and its hydroxylated metabolite (1,3-dimethyluric acid) were measured by high-pressure liquid chromatography, and Km and Vm,,, values were estimated. Enoxacin and ciprofloxacin selectively blocked the two N demethylations; they significantly inhibited the hydroxylation only at high concentrations. Norfloxacin and ofloxacin caused little or no inhibition of the three metabolites at comparable concentrations. The extent of inhibition was reproducible in five different human livers. Inhibition enzyme kinetics revealed that enoxacin caused competitive and mixed competitive types of inhibition. The oxo metabolite of enoxacin caused little inhibition of theophylline metabolism and was much less potent than the parent compound. Nonspecific inhibition of cytochrome P-450 was ruled out since erythromycin N demethylation (cytochrome P-450 mediated) was unaffected in the presence of enoxacin. These in vitro data correlate with the clinical interaction described for these quinolones and theophylline. We conclude that some quinolones are potent and selective inhibitors of specific isozymes of human cytochrome P-450 that are responsible for theophyiline metabolism. This in vitro system may be useful as a model to screen similar compounds for early identification of potential drug interactions.

show abstract

“…In vitro and clinical studies have consistently shown that enoxacin is the most potent inhibitor of xanthine metabolism, with marked reductions in theophylline and caffeine clearance of 41 to 74% and 78 to 79%, respectively (1,9,14,17,19,26,29,32,33). Ciprofloxacin and pefloxacin are intermediate in their ability to reduce xanthine clearance (about 30% reduction for both theophylline and caffeine)., while nalidixic acid, norfloxacin, ofloxacin, and fleroxacin have little or no influence on theophylline or caffeine disposition (3, 5, 6, 9-11, 16, 21, 25, 34).…”

Section: Discussionmentioning

confidence: 99%

Lack of interaction between lomefloxacin and caffeine in normal volunteers

Healy

Schoenle

Stotka

et al. 1991

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Sixteen healthy, nonsmoking adult males participated in a randomized, double-blind, placebo-controlled, two-way crossover study to evaluate the influence of chronic lomefloxacin administration on the disposition of caffeine and its major metabolite, paraxanthine, at steady-state conditions. Lomefloxacin (400 mg) or placebo was administered orally once daily for 5 days to xanthine-free volunteers after an overnight fast. Caffeine (200 mg orally) was administered simultaneously with lomefloxacin on days 3 through 5. After a 2-day washout period, subjects were crossed over to the alternate 5-day regimen with caffeine, which was again given on the final 3 days. Blood samples for caffeine, paraxanthine, and lomefloxacin concentration determinations were serially collected for 48 h following the last dose of each regimen. All compounds were analyzed by high-performance liquid chromatography. For the placebo versus lomefloxacin-containing treatments, maximum caffeine concentrations in plasma (4.35 0.63 versus 4.07 ± 0.56 ,ug/ml), areas under the concentrationtime curve from time zero to 24 h at steady state (30.3 ± 6.9 versus 29.7 ± 6.6 ,ug h/ml), and elimination half-lives of caffeine (4.8 ± 1.1 versus 4.8 ± 1.2 h) were not significantly different. In addition, there were no significant changes in the disposition parameters of paraxanthine as a result of lomefloxacin administration. The frequencies of central nervous system-related effects for the two treatments were not statistically different. We conclude that lomefloxacin has no significant effect on the disposition of caffeine in young healthy volunteers.Several quinolone antibiotics, including enoxacin, ciprofloxacin, and pefloxacin, have been reported to interfere with the clearance of methylxanthine compounds such as theophylline and caffeine, leading to elevated concentrations of the xanthine in serum (1,9,10,17,19,23,29,33,34) and, in the case of theophylline, central nervous system (CNS) toxicity (13,20,30,32). However, other quinolones such as norfloxacin, ofloxacin, and fleroxacin appear to have minimal or no effect on methylxanthine disposition (3,5,6,9,11,16,21,25,34).Lomefloxacin is an investigational difluoroquinolone that has a broad antimicrobial spectrum. Following oral administration, lomefloxacin is rapidly absorbed into the blood, widely distributed into peripheral tissues, and excreted into urine, primarily as the parent compound. It has a relatively long serum half-life (tl/2) of 6 to 8 h in volunteers with normal renal function (8). Recent studies have shown that lomefloxacin does not significantly interfere with theophylline kinetics (12,15,27). However, its effect on caffeine clearance has not been studied previously. The purpose of this study was to determine whether multiple oral doses of lomefloxacin alter the disposition of caffeine and its major metabolite, paraxanthine, at steady-state conditions in healthy volunteers.(Results of this study were presented at the

show abstract

Inhibition of the oxidative metabolism of theophylline in isolated rat hepatocytes by the quinolone antibiotic enoxacin and its metabolite oxoenoxacin, but not by ofloxacin

Cited by 20 publications

References 12 publications

Alteration of pharmacokinetics of cyclophosphamide and suppression of the cytochrome P450 genes by ciprofloxacin

Alteration of pharmacokinetics of cyclophosphamide and suppression of the cytochrome P450 genes by ciprofloxacin

In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes

Lack of interaction between lomefloxacin and caffeine in normal volunteers

Contact Info

Product

Resources

About