Omeprazole Ketoconazole

Fluconazole and voriconazole almost certainly cause a rise in omeprazole and esomeprazole levels by inhibiting their metabolism by the cytochrome P450 isoenzymes CYP2C19 and CYP3A4. As esomeprazole is an inhibitor of and also a substrate for CYP2C19, it is likely to have the same effect as omeprazole. Ketoconazole only inhibits CYP3A4 and therefore causes a less marked rise in omeprazole levels. Itraconazole would be expected to interact similarly to ketoconazole. 

Inhibitors Fluvoxamine Moclobemide fluvoxamine tranyl- cypromine Paroxetine Ketoconazole omeprazole grapefruitjuice... 

CYP2C19 Cimetidine, ketoconazole, omeprazole, ticlo-pidine"... 

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. 

Inhibitors Inducers pantoprazole Omeprazole, isoniazid, ketoconazole Barbiturates, rifampin... 

Gafni I, Nolte H, Tyndale R et al. (2001) Resolving the roles of CYP2C19 and CYP3A4 in the metabolism of omeprazole in vivo using chronic omeprazole and ketoconazole. Faseb Journal 15 A918... 

These findings explain some pharmacokinetic interactions of clobazam with ketoconazole (which inhibits the demethy-lation of clobazam by 70%) and omeprazole (which inhibits the hydroxylation of N-desmethylclobazam by 26%). In addition, in 22 patients with epilepsy who were genotyped for CYP2C19, there was a higher plasma metabolic ratio of N-desmethylclobazam clobazam in patients with one CYP2C19 2 mutated allele than in those with the wild-type genotype. 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

Omeprazole is a proton pump inhibitor. Headache, skin rash, and diarrhea have all been recorded by adverse event registries sufficiently often to suggest causal relations (1). Omeprazole is a modest inhibitor of CYP isoforms. Interactions are less likely than with cimetidine and are probably of no practical importance. However, omeprazole reduces the absorption of drugs that require a low gastric pH (ketoconazole, iron salts, ampicilhn) and can inhibit the hepatic clearance of some drugs (diazepam, warfarin, phenytoin) (2). 

Clinically important, potentially hazardous interactions with CYP3A4-inhibitors such as ketoconazole, omeprazole etc... 

Clinically important, potentially hazardous interactions with aluminum, aminophylline, aspirin, chlorambucil, cimetidine, clarithromycin, cyclophosphamide, cyclosporine, dicumarol, diuretics, docetaxel, estrogens, grapefruit juice, indomethacin, influenza vaccines, itraconazole, ketoconazole, lansoprazole, live vaccines, methotrexate, montelukast, omeprazole, oral contraceptives, pancuronium, phenobarbital, phenytoin, ranitidine, rifampicin, rifampin, timolol, tolbutamide, vitamin A... 

Cimetidine, fluconazole, fluoxetine, fluoxamine, ketoconazole, (iS)-mephenytoin, omeprazole, tranylcypromine... 

Acetaminophen, aldrin, alfentanil, amiodarone, aminopyrine, amitriptyline, amprenavir, androstenedione,antipyrine, astemizole, benzphetamine, budesonide, carbamazepine, celecoxib, chlorpromazine, chlorzoxazone, cisapride, clarithromycin, clozapine, cocaine, codeine, cortisol, cyclophosphamide,cyclosporin, dapsone, delavirdine, dextromethorphan, digitoxin, diltiazem, diazepam, erythromycin, 17j3-estradiol, ethinylestradiol, etoposide, felbamate, fentanyl, flutamide, hydroxyarginine, ifosphamide, imipramine, indinavir, ketoconazole, lansoprazole, loratidine, losartan, lovastatin, (iS)"mephen3d in, methadone, mianserin, miconazole, mifepristone, nelfinavir, nevirapine, nicardipine, nifedipine, odansetron, omeprazole, orphenadrine, proguanil, propafenone, quinidine, quinine, rapamycin, retinoic acid, ritonavir, saquinavir, selegiline, serindole, sufentanil, sulfinpyrazone, tacrolimus, tamoxifen, tamsulosin, taxol, teniposide, terfenadine, tetrahydrocannabinol, theophylline, toremifene, triazolam, trimethadone, trimethoprim, troleandomycin, verapamil, warfarin, zatosetron, Zolpidem, zonisamide... 

CYP2C19 <5 5 Amitriptyline S-mephenytoin Omeprazole Phenytoin Phenobarbital Propranolol Diazepam Fluoxetine Fluvoxamine Ketoconazole Omeprazole Ticlopidine Topiramate Carbamazepine Rifampin... 

Chronic treatment with omeprazole decreases the absorption of vitamin B12, but the clinical relevance of this effect is not clear. Loss of gastric acidity also may affect the bioavailability of such drugs as ketoconazole, ampicillin esters, and iron salts. 

Ketoconazole and other azoles Benzodiazepines, cisapride, cyclosporine, fluoxetine, lovastatin, omeprazole, quinidine, toibutamide, warfarin Risk of toxicity due to inhibition of metabolism of these drags... 

Yet another study used omeprazole to raise the pH and Coca-Cola Classic to lower it. Absorption was greatest when ketoconazole was given alone, and least when given with omeprazole. However, Coca-Cola increased the absorption of ketoconazole in the presence of omeprazole to 65% of that seen with ketoconazole alone. ... 

The bioavailability of ketoconazole is reduced by both omeprazole and rabeprazole. Other proton pump inhibitors are expected to behave similarly. Omeprazole also markedly reduces the absorption of itraconazole capsules, but not the oral solution. Proton pump inhibitors are predicted to reduce the bioavailability of posaconazole. The bioavailabilities of fluconazole and voriconazole are not significantly affected by omeprazole. Esomeprazole levels may also be Increased by voriconazole.Omeprazole levels are Increased by ketoconazole, and markedly increased by fluconazole and voriconazole. 

Based on data for omeprazole (see below), and the known acid-lowering effect of esomeprazole, the manufacturers predict that esomeprazole might reduce the absorption of itraconazole and ketoconazole, which depend on a low pH for optimal dissolution and absorption. Voriconazole may more than double the levels of esomeprazole. ... 

Ketoconazole. A three-way crossover study in 9 healthy fasting subjects found that omeprazole 60 mg reduced the AUC of ketoconazole 200 mg... 

Another study was carried out in 10 healthy subjects (both extensive and poor metabolisers) to find the extent to which cytochrome P450 isoenzyme CYP3A4 is involved in the metabolism (sulfoxidation) of omeprazole. This revealed that ketoconazole 100 to 200 mg, a known inhibitor of CYP3A4, reduced the formation of the omeprazole sulfone in both groups, and doubled the serum omeprazole levels in the poor metabolisers. ... 

The interaction between itraconazole and omeprazole also appears to be established, but it appears that this can be minimised by using an oral itraconazole solution. As with ketoconazole, giving itraconazole with an acidic drink such as cola , (p.215) would minimise the interaction, and is recommended by some manufacturers of itraconazole for patients taking proton pump inhibitors. " Monitor patients taking itraconazole if proton pump inhibitors are also given. The effect of itraconazole on omeprazole is unknown, but it might be expeeted to increase omeprazole levels similarly to ketoconazole. 

Bdttiger Y, Tybring G, Gotiiarson E, Bertilsson L. Inhibition of the sulfoxidation of omeprazole by ketoconazole in poor and extensive metabolizers of S-mephen3rtoin. Clin Pharmacol Ther 991) 62,384-91. 

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