Ciprofloxacin, metabolism

Elevations of serum transaminase concentrations generally are not correlated with the residual capacity of the liver to metabolize drugs, so these markers cannot be used directly as guides for residual metabolic capacity. Hepatically cleared TB drugs include isoniazid, rifampin, pyrazinamide, ethionamide, and p-aminosalicylic acid.39 Ciprofloxacin is about 50% cleared by... 

Metabolism of ciprofloxacin by Pestalotiopsis guepini yielded /V-acetylcipro-floxacin (the most abundant metabolite), desethylene-W-acetylciprofloxacin, A-formylciprofloxacin, and 7 -amino-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-... 

Ciprofloxacin/norfloxacin i Theophylline Decreased metabolism of theophylline Monitor theophylline... 

T Pancreatic insulin release Metformin Peripheral insulin sensitivity hepatic glucose output/production i intestinal glucose absorption Dose Ist-line (naive pts), 1.25/250 mg PO daily-bid 2nd-line, 2.5/500 mg or 5/500 mg bid (max 20/2000 mg) take w/ meals, slowly T dose hold before 48 h after ionic contrast media Caution [C, -] Contra SCr >1.4 mg/dL in females or >1.5 mg/dL in males hypoxemic conditions (sepsis, recent MI) alcoholism metabolic acidosis liver Dz Disp Tabs SE HA, hypoglycemia, lactic acidosis, anorexia, N/V, rash Additional Interactions T Effects W/ amiloride, ciprofloxacin cimetidine, digoxin, miconazole, morphine, nifedipine, procainamide, quinidine, quinine, ranitidine, triamterene,... 

Sustained-release formulations can produce stable serum concentrations with once or twice daily dosage. Therapeutic effects occur at blood levels > 5 mg/1, and side effects increase considerably at levels > 15 mg/1. Smoking, alcohol, anticonvulsants, and rifampicin induce the drug-metabolizing enzyme system in liver and reduce the half-life of theophylline. On the other hand, heart and liver failure, sustained fever, old age and drugs such as cimeti-dine, ciprofloxacin, and oral contraceptives reduce theophylline clearance and thereby increase serum concentrations. 

All quinolones interact with multivalent cations, forming chelation complexes resulting in reduced absorption. Major offenders are antacids vitamins containing calcium and iron can also be problematic. All fluoroquinolones interact with warfarin, didanosine (ddi), and phenytoin, resulting in decreased absorption or metabolism. Ciprofloxacin and other second-generation drugs interact with theophylline by decreasing its clearance, which leads to theophylline toxicity. 

Eszopiclone is metabolized in the liver by CYP 3A4. Eszopiclone should not be used in patients with severe hepatic impairment. Dose adjustment and caution are recommended in patients taking enzyme inhibitors such as ketoconazole, ciprofloxacin, erythromycin, iso-niazid, and nefazodone. Other sedative-hypnotics are not recommended with administration of this medication. 

Although it has been largely replaced by inhaled agonists, theophylline continues to be used for the treatment of bronchospasm by some patients with asthma and bronchitis (see Chapter 20). A dose of 20-30 tablets can cause serious or fatal poisoning. Chronic or subacute theophylline poisoning can also occur as a result of accidental overmedication or use of a drug that interferes with theophylline metabolism (eg, cimetidine, ciprofloxacin, erythromycin see Chapter 4). 

Caffeine [P] Ciprofloxacin, enoxacin, pipedemic acid, and to a lesser extent, norfloxacin, inhibit caffeine metabolism. 

Drugs that may inhibit cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexile-tine, miconazole, nefazodone, omeprazole, paroxetine, propoxyphene, quinidine, ritonavir, sulfamethizole, verapamil, voriconazole, zafirlukast, and zileuton. 

Since ciprofloxacin, the major metabolite of enrofloxacin, exhibits biological activity similar to that of the parent compound, it is also used as an individual fluoroquinolone drug. In this case, ciprofloxacin is metabolized mainly to oxociprofloxacin and desethylene ciprofloxacin (149). After oral administration to broiler chickens, ciprofloxacin was rapidly and efficiently absorbed, its metabolism being similar to that observed in other animal species. It has been reported that the mean tissue concentrations of ciprofloxacin and its metabolites that ranged between 5 and 26 ppb persisted in chickens up to 12 days after treatment (149). 

The pharmacokinetics of enrofloxacin and its active metabolite, ciprofloxacin, have been further extensively studied in sea bass after treatment by oral gavage or water, at a temperature of 15 C (157). Enrofloxacin was absorbed and eliminated slowly after oral administration to the sea bass. Following bath treatment, enrofloxacin efficiently penetrated fish tissues but it was poorly metabolized compared with mammals. On the other hand, ciprofloxacin was generally detected in very low concentrations (less than 0.02 ppm) in plasma samples after both oral and bath treatment. Liver levels of ciprofloxacin were found to be 0.12 ppm after a 5 ppm bathing for 24 h, 0.06 ppm after a 10 ppm bathing for 8 h, and 0.33 ppm after a 50 ppm bathing for 4 h, suggestive of hepatic metabolism of enrofloxacin. 

The interaction between the quinolone antibacterials and CYP1A2 has been studied in some depth for enoxacin and pefloxacin. Both compounds have been shown to inhibit CYPlA2-mediated metabolism of caffeine in vitro (49). This in vitro inhibition translated into a twofold decrease in caffeine clearance by pefloxacin and a sixfold decrease in clearance by enoxacin (50). Because pefloxacin undergoes N-demethylation to norfloxacin (51) and norfloxacin is much more potent as an inhibitor than pefloxacin (50), the observed in vivo interaction seen for pefloxacin may, in part, be due to norfloxacin. Many other quinolone antibacterial agents have been investigated for their interaction with theophylline, and ciprofloxacin has also been shown to have notable inhibitory effects (52). 

Robson RA, Begg EJ, Atkinson HC, et al. Comparative effects of ciprofloxacin and lomefloxacin on the oxidative metabolism of theophylline. Br J Clin Pharmacol 1990 29 491 193. 

Carolyn et al. have reported two additional ultraviolet-absorbing metabolites in urine specimens [12]. The drug is partially metabolized in the liver by modification of the piperazinyl group. Oxo-ciprofloxacin and tV-acetyl-ciprofloxacin microbial activities are comparable to norfloxacin, and desethylene-ciprofloxacin is comparable to nalidixic acid for certain organisms. About 40-50% of an oral dose is excreted unchanged in the urine, and 15% as metabolites. Upto 70% of a parental dose may be excreted unchanged, and 10% as metabolites within 24 h [13, 14]. 

Ciprofloxacin and its metabolite desethylene-ciprofloxacin were determined in human plasma using capillary electrophoresis in the presence of N-(l-naphthyl) ethylenediamine dihydrochloride as an internal standard. Krol et al. [15] have thoroughly investigated the biotransformation of ciprofloxacin in body fluids using high performance liquid chromatography (HPLC) and proposed the sequence of metabolic pathways illustrated in Figure 1. 

Ciprofloxacin is eliminated by renal and non-renal mechanisms. The drug is partially metabolized in the liver by modification of the piperazinyl group to atleast four metabolites. These metabolites, which have been identified as desethylene-ciprofloxacin, sulfo-ciprofloxacin, oxo-ciprofloxacin, and A-acetyl-ciprofloxacin, have microbiological activities that are less than that of the parent drug, but may be similar to or greater than that of some other quinolones [4, 8, 9]. 

Drug interactions The effect of antacids and cations on the absorption of these agents was considered above. Ciprofloxacin, ofloxacin and enoxacin can increase the serum levels of theophylline by inhibiting its metabolism. They also may raise levels of warfarin, caffeine and cyclosporine. Cimetidine interferes with the... 

The additive effect of a combination of antibiotics is one in which the effect of the combination is equal to that of the sum of the effects of the individual components. Additive effects probably occur when active metabolites are produced from an active parent compound, such as metabolism of enrofloxacin to ciprofloxacin [59]. 

PENTOXIFYLLINE ANTIBIOTICS Ciprofloxacin may t pentoxifylline levels Uncertain likely to be due to inhibition of hepatic metabolism Warn patients of the possibility of adverse effects of pentoxifylline... 

DULOXETINE ANTIBIOTICS -CIPROFLOXACIN t duloxetine levels with risk of side-effects, e.g. arrhythmias Inhibition of metabolism of duloxetine Avoid co-administration... 

ROPINIROLE CIPROFLOXACIN t ropinirole levels Inhibition of CYP1 A2-mediated metabolism Watch for early features of toxicity (nausea, drowsiness)... 

CLOZAPINE, OLANZAPINE CIPROFLOXACIN t clozapine levels and possibly t olanzapine levels Ciprofloxacin inhibits CYP1A2 clozapine is primarily metabolized by CYP1A2, while olanzapine is partly metabolized by it Watch for the early features of toxicity to these antipsychotics. A1 in dose of clozapine and olanzapine may be required... 

OPIOIDS CIPROFLOXACIN 1. Effects of methadone t by ciprofloxacin 2.1 levels of ciprofloxacin with opioids 1. Ciprofloxacin inhibits CYP1A2-, CYP2D6- and CYP3A4-mediated metabolism of methadone 2. Uncertain 1. Watch for t effects of methadone 2. Avoid opioid premedication when ciprofloxacin is used as surgical prophylaxis... 

TIZANIDINE ANTIBIOTICS-CIPROFLOXACIN T tizanidine levels Tizanidine is a substrate for CYP1A2 ciprofloxacin is a potent inhibitor of CYP1A2 and is thought to inhibit its presystemic metabolism, resulting in t absorption and t levels of tizanidine Avoid co-administration... 

A significant fraction of each drug is excreted unchanged in the urine (by glomerular filtration and tubular secretion, e.g. norfloxacin and ciprofloxacin). Sparfloxacin and trovafloxacin have significant non-renal elimination pathways. Hepatic metabolism also takes place (e.g. nalidixic acid being converted to an active metabolite). 

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