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

Sarkar, Mohamadi; Polk, Ron E.; Guzelian, Philip S.; Hunt, Charles E.; Karnes, H. Thomas

doi:10.1128/aac.34.4.594

Cited by 75 publications

(27 citation statements)

References 22 publications

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“…The elimination of certain metabolized drugs such as antipyrine, phenacetin, chlordiazepoxide and theophylline is increased in cigarette smokers [4][5][6][7][8][9][10][11][12]. Cytochrome P450IA2 (CYP1A2) is a major enzyme catalysing the metabolism of phenacetin [13,14] and theophylline [15][16][17]. Cigarette smoking induces mainly the P4501A enzyme family [13,18,19].…”

Section: Introductionmentioning

confidence: 99%

Cigarette smoking enhances the elimination of quinine

Wanwimolruk

Wong

Coville

et al. 1993

Brit J Clinical Pharma

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The pharmacokinetics of a single dose (600 mg) of quinine sulphate were examined in a group of non-smokers (n = 10) and in heavy cigarette smokers (n = 10). The mean (± s.d.) oral clearance of quinine in smokers (0.189 ± 0.075 1 h-1 kg-1) was significantly greater than in non-smokers (0.107 ± 0.045 1 h-1 kg-, P < 0.01). The unbound clearance of quinine which reflects activity of the drug-metabolizing enzyme, was considerably greater (1.5-fold) in the smokers than in the non-smoker subjects. The mean elimination half-life of quinine in smokers was 7.5 ± 1.4 (s.d.) h, significantly shorter (P < 0.005) than the mean value in non-smokers (12.0 ± 3.1 h). These results suggest that cigarette smoking enhances the elimination of quinine. The clinical significance of these findings is unknown but they indicate the need for caution in the administration of quinine to patients who are heavy cigarette smokers.

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Section: Introductionmentioning

confidence: 99%

Cigarette smoking enhances the elimination of quinine

Wanwimolruk

Wong

Coville

et al. 1993

Brit J Clinical Pharma

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“…It has been reported that some of the quinolone antibacterial agents cause a reduced velocity of caffeine and theophylline degradation in vivo (see below) (for a review, see reference 10) and in vitro (14,40). Furthermore, reductions in the antipyrine metabolism rate and the R-warfarin oxidation rate were observed in humans when quinolones were coadministered with these drugs (23,24,46).…”

mentioning

confidence: 99%

Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro

Fuhr

Anders

Mahr

et al. 1992

Antimicrob Agents Chemother

129

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Inhibition of cytochrome P450OL2 activity is an important adverse effect of quinolone antibacterial agents. It results in a prolonged half-life for some drugs that are coadministered with quinolones, such as theophylline. The objective of the study described here was to define the parameters for quantifying the inhibitory potencies of quinolones against cytochrome P4501A2 in vivo and in vitro and to investigate the relationship between the results of both approaches. Cytochrome P450IA2 activity in vitro was measured by using the 3-demethylation rate of caffeine (500 FM) in human liver microsomes. The inhibitory potency of a quinolone in vitro was determined by calculating the decrease in the activity of cytochrome P450IA2 caused by addition of the quinolone (500 ,uM) into the incubation medium. The mean values (percent reduction of activity without quinolone) were as follows: enoxacin, 74.9%Yo; ciprofloxacin, 70.4%; nalidixic acid, 66.6%; pipemidic acid, 59.3%; norfloxacin, 55.7%; lomefloxacin, 23.4%; pefloxacin, 22.01%; amifloxacin, 21.4%; difloxacin, 21.3%; ofloxacin, 11.8%; temafloxacin, 10.01%; fleroxacin, no effect. The inhibitory potency of a quinolone in vivo was defined by a dose-and bioavailablity-normalized parameter calculated from changes of the elimination half-life of theophylline and/or caffeine reported in previously published studies. Taking the pharmacokinetics of the quinolones into account, it was possible to differentiate between substances with and without clinically relevant inhibitory effects by using results of in vitro investigations. The in vitro test described here may help to qualitatively predict the relevant drug interactions between quinolones and methylxanthines that occur during therapy.The fluoroquinolones have proven to be very effective antibacterial agents (2,20,23). Several new agents have been developed over the past decade. Their efficacies in controlling bacterial infections have resulted in the widespread use of these drugs.Another important biological effect of this drug class concerns the metabolism of several unrelated pharmaceutical agents, resulting in occasional adverse reactions. It has been reported that some of the quinolone antibacterial agents cause a reduced velocity of caffeine and theophylline degradation in vivo (see below) (for a review, see reference 10) and in vitro (14,40). Furthermore, reductions in the antipyrine metabolism rate and the R-warfarin oxidation rate were observed in humans when quinolones were coadministered with these drugs (23,24,46).In investigations with human liver microsomes, the mechanism of this interaction was determined for ofloxacin, ciprofloxacin, enoxacin, lomefloxacin, and pipemidic acid. A

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“…Consequently, specific hepatic cytochrome P450 enzymes may be more sensitive to the effects of IFNao. TH is metabolized principally by the CYP1A2 isozyme [25][26][27][28][29][30], although other isozymes may also play a role [27,31]. Studies of selective induction and inhibition of AP metabolic pathways suggest that AP is also metabolized by several isozymes [32,33], one of which may be common to the metabolism of theophylline [15].…”

Section: Discussionmentioning

confidence: 99%

Effects of interferon‐alpha monotherapy on hepatic drug metabolism in cancer patients.

Israel¹,

Blouin²,

McIntyre³

et al. 1993

Brit J Clinical Pharma

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1. The influence of interferon‐alpha (IFN alpha) on the clearances of theophylline (TH), antipyrine (AP) and hexobarbitone (HB) was studied in seven cancer patients given IFN alpha as their only treatment. In addition, IFN alpha effects on drug clearance were correlated with changes in serum inflammatory cytokines and acute phase proteins. 2. A 'baseline' study was performed by administering an oral drug 'cocktail' of TH (150 mg), AP (250 mg) and HB (250 mg) with saline injected simultaneously and again 24 h later. One week later, an 'acute' study was performed at the initiation of IFN alpha therapy, 3 × 10(6) units injected with the drug cocktail and again 24 h later. After 2 weeks of IFN alpha treatment three times per week, a 'chronic' study was performed with IFN alpha injected the day prior to, simultaneously with, as well as 24 h after the drug cocktail. 3. Plasma samples were collected over 48 h and the clearances of TH, AP and HB were estimated. Serum samples were collected at various times for the measurement of tumor necrosis factor (TNF), interleukin‐1 (IL‐1), interleukin‐6 (IL‐ 6), C‐reactive protein (C‐RP) and alpha 1‐acid glycoprotein (AGP). 4. IFN alpha caused a 33% decrease in the oral clearance of TH during the chronic study compared with baseline (P < or = 0.05). Although IFN alpha inhibited TH clearance by 16% during the acute study and AP clearance by 20‐21% during both acute and chronic studies, these changes did not reach statistical significance. IFN alpha caused minimal changes in HB clearance. There were no chronic effects of IFN alpha on serum cytokines or acute phase proteins. 5. The findings confirm that the most commonly used dose of IFN alpha inhibits the hepatic clearance in humans of some but not all drugs and that this inhibition persists during IFN alpha therapy. Because inhibition was not associated with increases in serum cytokines or acute phase proteins, the mechanism by which IFN alpha inhibits cytochrome P450 activities in vivo does not appear to involve inflammatory mediators such as TNF. IL‐1 or IL‐6.

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

Cited by 75 publications

References 22 publications

Cigarette smoking enhances the elimination of quinine

Cigarette smoking enhances the elimination of quinine

Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro

Effects of interferon‐alpha monotherapy on hepatic drug metabolism in cancer patients.

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