Lack of Effect of Ofloxacin on Theophylline Pharmacokinetics in Rats

Okazaki, Osamu; Miyazaki, Keiko; Tachizawa, Haruo

doi:10.1159/000238528

Cited by 12 publications

(7 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the previous study, we have reported that enoxacin pretreatment with five oral doses of 50 mg/kg over a period of 3 days extremely raises serum concentrations of theophylline in rats [3]. Considering the present results, it is conceivable that this elevation of serum theophylline concen trations is induced only by the inhibition of the metabolism of theophylline medi ated by cytochrome P-450-dependent monooxygenase system.…”

Section: Discussionsupporting

confidence: 58%

“…Thus, it has been reported that die concurrent administration of enoxacin remarkably raises plasma theophylline concentrations and induces untoward ad verse reactions with theophylline in hu mans [1,2]. With respect to the mechanism of enoxacin interaction with theophylline, the present authors have elucidated re cently that enoxacin extremely raises serum theophylline concentrations and re sults in a significant effect on the theo phylline pharmacokinetics by the inhibi- tion of hepatic microsomal cytochrome-P-450-dependent monooxygenases, the drug-metabolizing enzyme system, in rats [3]. Recently, it has been reported that cimetidine, a typical inhibitor of the drugmetabolizing enzyme system, has the abil ity to induce the enzyme systems by re peated administration, and to modify the effectiveness of concurrent drugs [4,5].…”

Section: Introductionmentioning

confidence: 60%

See 1 more Smart Citation

Effect of New Quinolones on Drug-Metabolizing Enzyme System of Rat Hepatic Microsomes

Okazaki

Kurata

Tachizawa³

1988

Chemotherapy

Self Cite

View full text Add to dashboard Cite

Effects of repeated oral administration of new quinolones, ofloxacin, enoxacin and norfloxacin, once daily for 7 days, on the drug-metabolizing enzyme system of rat hepatic microsomes were studied in comparison with that of phenobarbital, a potent inducer of cytochromes P-450. Treatment of phenobarbital at the oral dose of 120 mg/kg induced significant increases in the contents of cytochrome P-450, cytochrome b₅and NADPH-cytochrome P-450 reductase and in the activity of ethoxycou-marin O-deethylase, and significant decreases in the activities of benzphetamine N-de-methylase and aniline hydroxylase. However, ofloxacin, enoxacin and norfloxacin at the oral dose levels of 80 and 320 mg/kg showed no significant effect on the content of each constituent of the drug-metabolizing enzyme system, and the three enzyme activities. Thus, it is concluded that new quinolones including ofloxacin have no ability to induce a cytochrome-P-450-dependent monooxygenase system.

show abstract

Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 60%

Effect of New Quinolones on Drug-Metabolizing Enzyme System of Rat Hepatic Microsomes

Okazaki

Kurata

Tachizawa³

1988

Chemotherapy

Self Cite

View full text Add to dashboard Cite

show abstract

“…For enoxacin, toxicities apparently related to increased serum theophylline concentrations resulted in cessation of quinolone therapy in 9 of 15 patients (144). Evidence suggested that the mechanism of the drugdrug interaction was interference with demethylation of theophylline by the hepatic P450 enzymes by the 4-oxoquinolone metabolite (189,557,836). Notably, clinically important drug-drug interactions did not occur between theophylline and either norfloxacin (76,348,543,836) or ofloxacin (242,309,543,836).…”

Section: Drug-drug Interactionsmentioning

confidence: 99%

Fluoroquinolone antimicrobial agents

1989

View full text Add to dashboard Cite

The fluoroquinolones, a new class of potent orally absorbed antimicrobial agents, are reviewed, considering structure, mechanisms of action and resistance, spectrum, variables affecting activity in vitro, pharmacokinetic properties, clinical efficacy, emergence of resistance, and tolerability. The primary bacterial target is the enzyme deoxyribonucleic acid gyrase. Bacterial resistance occurs by chromosomal mutations altering deoxyribonucleic acid gyrase and decreasing drug permeation. The drugs are bactericidal and potent in vitro against members of the family Enterobacteriaceae, Haemophilus spp., and Neisseria spp., have good activity against Pseudomonas aeruginosa and staphylococci, and (with several exceptions) are less potent against streptococci and have fair to poor activity against anaerobic species. Potency in vitro decreases in the presence of low pH, magnesium ions, or urine but is little affected by different media, increased inoculum, or serum. The effects of the drugs in combination with a beta-lactam or aminoglycoside are often additive, occasionally synergistic, and rarely antagonistic. The agents are orally absorbed, require at most twice-daily dosing, and achieve high concentrations in urine, feces, and kidney and good concentrations in lung, bone, prostate, and other tissues. The drugs are efficacious in treatment of a variety of bacterial infections, including uncomplicated and complicated urinary tract infections, bacterial gastroenteritis, and gonorrhea, and show promise for therapy of prostatitis, respiratory tract infections, osteomyelitis, and cutaneous infections, particularly when caused by aerobic gram-negative bacilli. Fluoroquinolones have also proved to be efficacious for prophylaxis against travelers' diarrhea and infection with gram-negative bacilli in neutropenic patients. The drugs are effective in eliminating carriage of Neisseria meningitidis. Patient tolerability appears acceptable, with gastrointestinal or central nervous system toxicities occurring most commonly, but only rarely necessitating discontinuance of therapy. In 17 of 18 prospective, randomized, double-blind comparisons with another agent or placebo, fluoroquinolones were tolerated as well as or better than the comparison regimen. Bacterial resistance has been uncommonly documented but occurs, most notably with P. aeruginosa and Staphylococcus aureus and occasionally other species for which the therapeutic ratio is less favorable. Fluoroquinolones offer an efficacious, well-tolerated, and cost-effective alternative to parenteral therapies of selected infections.

show abstract

“…However, the in vitro experiments in this study showed that ENX and NFLX inhibited the 7-EC 0-deethyl ase activity in liver microsomes even from the beginning of the reaction; at that time, no metabolite could have been produced from the parent drugs. Okazaki et al (26) have also reported similar results from in vitro experi ments. Recently, Mulder et al (28) inves tigated the effects of ENX, its metabolite oxoenoxacin and OFLX on the oxidative metabolism of theophylline in isolated rat hepatocytes.…”

Section: Discussionmentioning

confidence: 52%

“…Plasma protein binding and renal clearance of theophylline are reported to remain unchanged in patients treated with ENX or OFLX (1,2,5), so that the prolongation of the TI/2 of theophylline is considered to be due to reduced metabolic clearance in the liver. In rats, ENX and OFLX are also reported not to affect serum protein binding (26).…”

Section: Discussionmentioning

confidence: 92%

Comparison of Inhibitory Effects of New Quinolones on Drug Metabolizing Activity in the Liver

Nakanishi

Okuno

1990

Japanese Journal of Pharmacology

View full text Add to dashboard Cite

Abstract-The effects of three new quinolones (enoxacin (ENX), norfloxacin (NFLX) and ofloxacin (OFLX)) on acetaminophen-induced liver injury in rats were examined and compared with their effects on the elimination half-life (T1/2) of theophylline (in vivo) and on the 7-ethoxycoumarin (7-EC) O-deethylase activity in liver microsomes (in vitro).ENX, NFLX and OFLX (75 or 300 mg/kg) were administered orally to rats 1 hr before, simultaneously with, and 1 hr after the acet aminophen injection (800 mg/kg). Biochemical liver function tests, drug me tabolizing activity in liver microsomes, the total glutathione content of the liver and histological changes were examined 5 hr after the acetaminophen injection. ENX markedly reduced acetaminophen-induced liver injury and NFLX slightly but sig nificantly did so, but no protective effect was observed with OFLX treatment. ENX markedly and NFLX slightly prolonged the T1/2 of theophylline, but OFLX did not affect it. In addition, ENX markedly and NFLX slightly inhibited the 7-EC Odeethylase activity in liver microsomes, but OFLX again had no effect. These findings indicated that ENX markedly inhibited the activity of cytochrome P-450 in liver microsomes and NFLX did so slightly, while OFLX had no such effect. Slight variations in the structures of these quinolones might explain the differences in their effects on cytochrome P-450 activity.In recent years, several new quinolones have been developed as effective antibacterial agents and widely used to treat a variety of infections. In 1984, Wijnands et al. (1) first reported that co-administration of enoxacin (ENX), one of the new quinolones, with theophylline raised the plasma theophylline concentration, and that eight of the ten pa tients who received theophylline in combina tion with ENX developed serious nausea and vomiting. Since then, many investigators have demonstrated that ENX raises the plasma theophylline concentration and prolongs its elimination half-life (T1 /2). In contrast, other new quinolones, such as norfloxacin (NFLX) and ofloxacin (OFLX), have no or only a slight effect on the pharmacokinetics of theophyl line (2-8). It appears that the increase in the plasma theophylline concentration is due to a reduced metabolic clearance of theophylline in the liver induced by ENX, while NFLX and OFLX seem to have little effect on drug metabolizing activity in the liver. However, little in vitro evidence has been reported that the new quinolones affect the activity of drug metabolizing enzymes in liver microsomes.Cimetidine, which is known to inhibit the drug metabolizing activity in liver microsomes (9), has been reported to prevent acetamino phen-induced liver injury (10, 11), but there have been no reports concerning the effects of the new quinolones on acetaminophen induced liver injury.In the present study, the protective effects of three new quinolones (ENX, NFLX and OFLX) on acetaminophen-induced acute liver injury in rats were investigated and com pared with each other. Moreover, the effects of these new quinolone...

show abstract

Lack of Effect of Ofloxacin on Theophylline Pharmacokinetics in Rats

Cited by 12 publications

References 17 publications

Effect of New Quinolones on Drug-Metabolizing Enzyme System of Rat Hepatic Microsomes

Effect of New Quinolones on Drug-Metabolizing Enzyme System of Rat Hepatic Microsomes

Fluoroquinolone antimicrobial agents

Comparison of Inhibitory Effects of New Quinolones on Drug Metabolizing Activity in the Liver

Contact Info

Product

Resources

About